neuroinflammatory hypothesis of depression

• Open access
• Published: 16 February 2021

On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?

• Elnaz Roohi 1 ,
• Nematollah Jaafari 2 &
• Farshad Hashemian 1  

Journal of Neuroinflammation volume  18 , Article number:  45 ( 2021 ) Cite this article

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Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.

Major depressive disorder (MDD) is a leading cause of disability throughout the world with a global prevalence of 2.6–5.9% [ 1 ]. The total estimated number of people living with depression worldwide increased by 49.86% from 1990 to 2017 [ 2 ]. According to worldwide projections, MDD will be the single major cause of burden of all health conditions by 2030 [ 3 ]. MDD is characterized by periods of low mood, altered cognition, considerable functional burden including impaired occupational functioning and psychosocial disability [ 4 ]. Despite available pharmacotherapeutic options, 30–60% of patients with MDD are not responsive to available treatments [ 5 ] and the rate of remission of the disease is often < 50% [ 6 ], while recurrence rates are more than 85% within 10 years of a depressive episode, and average about ≥ 50% within 6 months of assumed clinical remission [ 4 ]. Indeed, there exists no compelling evidence that current treatments are capable of disease modification in MDD patients. Thus, therapeutic deficiency in treatment outcomes reflects the demand for revitalizing psychiatric therapeutics with novel pharmacotherapeutic options that engage non-monoaminergic molecular targets.

A large body of evidence suggests that inflammation has central role in pathogenesis of MDD [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, the exact mechanisms underlying inflammation-induced depression are not completely elucidated [ 3 ]. Historically, the “monoamine-depletion hypothesis” has been the main proposed pathophysiology [ 14 ]; nevertheless, this hypothesis alone cannot fully account for pathogenesis of MDD [ 15 , 16 ]. In recent years, “inflammatory hypothesis” has been proposed [ 17 ]. However, it is noteworthy that it was probably in the early 1990s that for the first time, possible relationships between the peripheral immune system and major depression was studied [ 18 ]. Maes et al. (1992) established immune cell profile of patients with depression and advocated for the existence of a systemic immune activation during major depressive disorder [ 19 ]. Moreover, correlations between IL-6 activity, acute phase proteins, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis were suggested in severe depression [ 20 ].

Most proximally, inflammation is regulated by expression of immune response genes including interleukin (IL)-1B, tumor necrosis factor (TNF), and IL-6 which promote secretion of pro-inflammatory cytokines leading to systemic inflammation. Distally, inflammation is regulated in the brain where socio-environmental cues including possible threat are detected. This neuro-inflammatory link can activate the conserved transcriptional response to adversity (CTRA) before happening of a possible threat or bacterial infection. However, the negative aspect of central regulation of systemic inflammation is that it can give social and foreseen dangers (including those that have not yet occurred or may never actually happen) the ability to activate the CTRA in the absence of actual physical danger. Under normal conditions, CTRA-related inflammatory activity is downregulated by the HPA axis via the production of cortisol. Nevertheless, when prolonged actual or perceived social threat or physical danger is present, glucocorticoid resistance can develop which leads to excessive inflammation that heightens a person’s risk for development of several disorders including MDD, especially if activation of these pathways is prolonged [ 21 ]. As mentioned above, the current understanding of MDD encloses not only alterations in neurotransmitters, but also changes in immune and endocrine functioning as well as neural circuits [ 22 ]. This broadened framework has just started to inform a wide array of novel, personalized therapeutics that are showcasing great promise in a new holistic approach to MDD [ 23 ].

Cytokines are implicated in pathogenesis of MDD [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Risk factors of developing MDD include familial, developmental, psychological, and medical risk factors as well as molecular factors associated with genetics, epigenetics, gene expression, and also those related to the endocrine and the immune system [ 31 , 32 ]. All these risk factors have been shown to be related with changes in cytokine production or signaling. In other words, cytokines are involved in almost every predisposing or precipitating risk factor associated with MDD [ 24 ]. Indeed, there is accumulating evidence in favor of involvement of pro-inflammatory cytokines in pathophysiology of depression [ 24 , 29 , 33 , 34 , 35 , 36 ]. Various studies reported higher levels of multiple inflammatory markers including IL-6 in patients with MDD [ 37 , 38 , 39 , 40 , 41 ]. Of all pro-inflammatory cytokines, changes in IL-6 serum levels have been reported as one of the most reproducible abnormalities in MDD [ 38 ].

The aim of the present narrative review is to elucidate the fundamentals, implications, challenges of cytokine research specifically IL-6 in major depressive disorder. This comprises of the following:

-) A Brief overview of cytokines

-) Cytokine categories according to immunological function.

-) IL-6 as a pleiotropic cytokine.

-) Brief overview of chemokines and their role in Depression.

-) Challenges of cytokine research in psychiatry.

-) IL-6 alterations in depression.

-) Effects of IL-6 on neurotransmitters’ synthesis, signaling, metabolism, and function.

-) Effects of IL-6 levels on brain morphology in depression.

-) Blockade of IL-6 and its receptor in the periphery as a potential therapeutic option in MDD.

-) Possible role of IL-6 together with gut microbiota in pathogenesis of depression.

-) Elevated levels of IL-6 in patients with COVID-19 infection.

The present article is a narrative review. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. We selected articles on the basis of being comprehensive, innovative, and informative for an in-depth understanding and a critical debate on the topic. Publications between 1973 and 2020 were included.

A brief overview of cytokines

Cytokines are a broad category of released proteins that act as signaling molecules to regulate inflammation and cellular activities [ 24 , 42 ]. They are produced by different immune cells (e.g., macrophages, lymphocytes, mast cells), parenchymal cells, endothelial and epithelial cells, fibroblasts, adipocytes, and stromal cells within the periphery [ 24 , 43 ]. Additionally, they are produced by microglia, astrocytes, and neurons in the brain [ 44 ]. Cytokines from the periphery (peripherally produced cytokines) can exert influences on inflammatory processes in the brain [ 45 , 46 ]. Indeed, they can enter blood-brain barrier (BBB) and affect the brain via humoral (accessing the brain through leaky secretions of the BBB such as choroid plexus), neural (through stimulation of primary afferent nerve fibers in the vagus nerve), and cellular (through stimulation of microglia by pre-inflammatory cytokines to produce monocyte chemottractant protein-1 and recruit monocytes to the brain) pathways [ 47 ]. Most cytokines function in their immediate microenvironment. Few of them are involved in paracrine signaling which indeed is fundamental to the control of an inflammatory response within a given tissue or organ and the activation of a coordinated immune response that involves multiple cell types [ 48 ]. Apart from navigating the immune system to defend the body from pathogens, cytokines have a modifying effect on neurotransmission [ 49 ].

It’s also noteworthy that the same cytokines can be produced by multiple cell types. For example, white blood cells, endothelium, fat cells, and other cells can produce TNF-α [ 50 ]. Additionally, one single cell can release different cytokines. For instance, T Helper type 2 (T H 2) cells can produce IL-3, IL-4, IL-5, IL-6, and IL-13 [ 24 ]. Cytokines can have pleiotropic, redundant, synergistic, and antagonistic effects [ 51 ]. The phenomenon that a single cytokine can act on several different cell types is called pleiotropy [ 51 ]. For instance, IL-10 can activate T H 2 cells and B cells, yet inhibit macrophages and T helper type 1 (T H 1) cells. Thus, being immunostimulatory as well as being immunosuppressive [ 52 ]. Cytokines are redundant in their activity, i.e., similar functions can be exerted by different cytokines. For instance, interferon (IFN)-γ, IL-2, and TNF-α enhance cellular immunity and production of cytotoxic cell contacts [ 53 ]. Cytokines can also act synergistically, i.e., they can have combined effects when acting together. For instance, IL-3 and IL-4 amplify each other’s effects to induce growth, differentiation, and activation of mast cells in a synergistic manner [ 24 ]. Another phenomenon in cytokines signaling is antagonism. An example of cytokine antagonism is that cytokines of the IL-1 superfamily can antagonize IL-18 effects [ 54 ].

Cytokine categories according to immunological function

Four categories of cytokines are usually referred to in psychoimmunological literature. (1) T H 1 cytokines (IL-2, IL-12, IFN-γ) which induce cytotoxic cell contacts. (2) T H 2 cytokines (IL-4, (IL-5, IL-13) which lead to production of antibodies. (3) Pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-17, IL-21, IL-22, IFN-α, TNF-α) which further the progress of inflammation. (4) Anti-inflammatory cytokines (IL-10, transforming growth factor-beta (TGF)-β which are influenced by regulatory T cells and impede inflammatory process from escalating [ 24 ]. However, these categories are not distinct and it must be considered that cytokines can exert various effects on different cells and therefore, they may have pro- and also anti-inflammatory properties. For instance, IFN-α which has been listed as a pro-inflammatory cytokine can also have anti-inflammatory properties [ 55 ].

IL-6 as a pleiotropic cytokine

IL-6 was first identified as a differentiation factor for B cells which stimulates production of antibodies by activated B cells. Apart from regulation of acute inflammation, IL-6 is known to induce differentiation of B cells, and activation and population expansion of T cells [ 56 ]. Within the peripheral and central nervous system (CNS), IL-6 can act as a neuronal growth factor inducing neurite development and nerve regeneration [ 57 ]. IL-6 receptor (IL-6R) consists of the IL-6-binding chain which has two forms of transmembrane IL-6R and soluble IL-6R (sIL-6R) [ 58 ] and a gp130 signal-transducing chain [ 59 ]. Following binding to its receptor (IL-6R), IL-6 initiates to exert its multiple functions.

It is quite interesting that IL-6 exerts both pro- and anti-inflammatory properties [ 60 , 61 ]. Indeed, its signaling is complex and can lead to both inflammatory and anti-inflammatory cascades depending upon the presence of either IL-6 receptor (IL-6R) or the membrane bound gp130 signal transducer and these are expressed at very different frequencies within specific cell type in the body [ 5 ]. Trans-signaling of IL-6, in which the soluble form of the IL-6 receptor (sIL-6R) is shed from the membrane bound receptors, is known to be pro-inflammatory [ 62 ]. The sIL-6R binds to IL-6 and is transported to any cell type on which gp130 is expressed [ 63 ]. While most soluble receptors (e.g., soluble receptor for TNFα) result in antagonistic action by competing for the ligand, the sIL-6R is agonistic and increases the types of cells through which IL-6 can signal. Additionally, IL-6 engages in classical signaling which is anti-inflammatory [ 63 ] and occurs through binding of IL-6 to the membrane bound cell surface receptor. Classical signaling of IL-6 solely occurs on some subsets of T cells, neutrophils and monocytes megakaryocytes, and hepatocytes [ 64 ]. In both classical and trans-signaling, the IL-6/IL-6R/gp130 complex uses two pathways to activate intracellular signaling namely the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway [ 5 ].

Indeed, IL-6 has been mostly regarded as having pro-inflammatory properties; however, it has many anti-inflammatory functions which are necessary for resolution of inflammation [ 65 ]. For instance, IL-6 inhibits activity of the transcription factor named nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and expression of the chemokine receptor on dendritic cells which is needed for recruiting these cells to lymphoid tissues; thus, involving in resolution of inflammation [ 66 ]. Research findings showed that IL-6 has a crucial role in regulation of T helper17 (Th17)/regulatory T (Treg) cells [ 67 ]. In the presence of TGF-β, IL-6 is a vital signal for differentiation of naive T cells into Th17 cells which in turn are implicated in induction of autoimmune diseases [ 68 , 69 ], and result in local tissue injury in chronic inflammatory disorders [ 70 ]. On the contrary, IL-6 can strongly inhibit the TGF-β-induced differentiation of Treg cells which in turn results in inhibition of autoimmunity and protects against tissue damage [ 71 ]. Functional dichotomy of IL-6 indicates that it may be responsible for maintaining the balance between pro- and anti-inflammatory responses, while having tissue-specific properties at the periphery and in the CNS [ 72 ].

Brief overview of chemokines and their role in depression

Chemokines are small chemotactic cytokines that are identified to have significant roles in migration of immune cells, induction of direct chemotaxis, and propagation of inflammatory responses [ 73 ]. They are classified into four sub-families based on their structural criteria (i.e., the number and spacing of their two N-terminals, disulfide bonding participating cysteine residues). These four subfamilies include CXC, CC, C, and CX3C [ 74 ]. Furthermore, they can be categorized according to their biological activity, namely, the maintenance of homeostasis and the induction of inflammation. There are also chemokines which have dual functionality [ 75 ].

These small chemotactic cytokines are known to be secreted in response to inflammatory cytokines; thereafter, selectively recruiting lymphocytes, monocytes, and neutrophil-inducing chemotaxis by activating G-protein-coupled receptors (GPCRs) [ 76 ]. A growing body of evidence suggests that chemotactic cytokines are implicated in neurobiological processes relevant to psychiatric disorders such as synaptic transmission and plasticity, neuroglia communication, and neurogenesis [ 77 ]. Indeed, disruption of any of the mentioned functions which may take place by activation of the inflammatory response system has consistently been found to be relevant in pathogenesis of depression [ 73 ].

There are indeed both pre-clinical and clinical evidence in support of linking alterations in the chemokine network to depressive behavior [ 73 ]. In an animal model of depression, namely prenatal stressed rats, levels of CCL2, and CXCL12 chemokines were found to be upregulated in the hippocampus and prefrontal cortex, which was indeed suggestive of excessive microglial activation [ 78 ]. Additionally, Trojan et al. (2017) investigated the modulatory properties of chronic administration of anti-depressants on the chemokines. According to their results, chronic administration of anti-depressants has been shown to normalize the prenatal stress-induced behavioral disturbances together with the observed alterations in CXCL12 and their receptor. Indeed, they concluded that alterations of CXCL12 and their receptor and at less extend changes in CX3CL1–CX3CR1 expression will probably be normalized following chronic treatment with anti-depressants [ 79 ].

Moreover, several clinical studies found correlations between elevated levels of circulating inflammatory chemokines and depressive symptoms in patients with major depressive disorder [ 73 , 80 , 81 , 82 , 83 ]. According to the results of a comprehensive meta-analysis, peripheral concentrations of a number of chemokines including CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, and CXCL8 can potentially discriminate between individuals with depression and those without [ 84 ]. Additionally, Ślusarczyk et al. (2016) provided a comprehensive account of the role of chemokines in processes underlying depressive disorder [ 85 ].

Challenges of cytokine research in psychiatry

There are some difficulties faced by researchers in conducting cytokine research in psychiatry. The major problem seems to be heterogeneity of the obtained results. In other words, research outcomes are conflicting and challenging to interpret [ 24 ]. Moreover, research in this area is largely based on measurement of cytokine levels in the periphery and it is not completely clear how serum or plasma levels of cytokines reflect the situation in the brain [ 47 ]. Compellingly, results of studies that examined both peripheral and CFS levels of IL-6 found no correlations between the mentioned measures; thus, suggesting that peripheral levels of IL-6 may not directly reflect central IL-6 levels [ 86 , 87 ].

It is also noteworthy that some environmental, social, biological, and medical factors may influence peripheral cytokine changes. For instance, one of the characteristics of obesity is chronic inflammation with the increased circulating levels of cytokines [ 88 , 89 ]. Indeed, adipose tissue is reported to build up and activate lymphocytes and macrophages that secrete inflammatory factors [ 89 , 90 ]. Interestingly, obese people show behavioral symptoms such as MDD and cognitive dysfunction at an increased rate in comparison with the general population [ 91 , 92 ]. Therefore, one may argue that alterations in cytokine levels are somehow unspecific [ 24 ]. Additionally, there is a considerable overlap in cytokine values between patients in the acute phase of depression, patients in remission, and patients who are recovered [ 24 ]. Although the use of cytokines as potential biomarkers of depression has been discussed frequently in various studies, cytokine changes have been reported in other psychiatric disorders as well. For instance, increased levels of pro-inflammatory cytokines have been reported in generalized anxiety disorder [ 93 , 94 , 95 ], obsessive-compulsive disorder [ 96 ], posttraumatic stress disorder [ 97 , 98 ], and sleep disorder [ 99 ].

Moreover, cytokine levels change during pharmacotherapy of depression. Indeed, it has been suggested that treatment with anti-depressants can potentially lead to alteration in peripheral levels of cytokines. According to the results of a meta-analysis, anti-depressants, overall, cause decrease in peripheral levels of IL-6, IL-10, and TNF-α [ 100 ]. However, anti-psychotics which are used in psychotic depression, especially those with the highest risk of weight gain (e.g., clozapine and olanzapine), cause significant increase in the blood levels of pro-inflammatory cytokine [ 101 ]. Additionally, mood stabilizers such as lithium and carbamazepine have also been linked with an increase in the peripheral levels of cytokines [ 102 ]. In sum, as cytokine signaling often exhibits pleiotropic, redundant, synergistic, and antagonistic effects, it seems to be advisable to consider all cytokines that work together or against each other and therefore, take into account the whole range of cytokines instead of a single one.

On the role of interleukin-6 in depression

Il-6 alterations in depression.

A growing body of evidence suggests that IL-6 has a crucial role in pathogenesis of depression [ 3 ] and is the most consistently increased cytokine in blood samples of MDD patients [ 38 , 103 ]. The first promising evidence for the role of IL-6 in occurrence of depression is most probably provided by a longitudinal study in which children with higher circulating levels of IL-6 at age 9 were found to be at a 10% greater risk of developing MDD by age 18, compared to the general population or children with low IL-6 levels. Indeed, the researchers concluded that inflammation and high IL-6 levels possibly predate the occurrence of depression [ 104 ]. Another evidence for potential role of IL-6 in depression is that peripheral levels of IL-6 were found to be positively correlated with symptom severity in anti-depressant non-responders [ 105 ].

Stress-based preclinical models of depression showed that IL-6 levels are increased following the onset of depression-associated behaviors. Rodents who were exposed to chronic mild stress exhibited anhedonia and elevated circulating levels of pro-inflammatory cytokines including IL-6 [ 106 , 107 ]. Moreover, in another study on male Wistar rats, serum levels of pro-inflammatory cytokines including IL-6 were reported to be higher in acute and restraint stress compared to non-stressed rats [ 108 ]. It is also noteworthy that some studies reported no significant alteration in peripheral levels of IL-6 in chronic mild stress models of depression [ 109 ]. Nevertheless, they reported elevated CNS levels of other inflammatory markers which probably reflects a time-dependent shift from peripheral to central cytokine activation or potential transport of the peripheral cytokines into CNS [ 109 ]. Another promising evidence was provided by studies on IL-6 knockout mice. Indeed, they were reported to be resistant to the development of depression-like phenotype following long-term light deprivation in the constant darkness, proposing a functional role for IL-6 in stress susceptibility [ 110 ]. Moreover, Ślusarczyk et al. (2015) found evidence for the role of prenatal stress as a priming factor that could exhibit effects on microglial cells and consequently lead to depressive-like disturbances in adult rat offspring. According to their results, the release of pro-inflammatory cytokines including IL-6 is enhanced in microglia obtained from prenatally stressed animals compared to control animals [ 78 ].

In fact, not every individual exposed to prolonged or acute stress develops a psychiatric disorder [ 111 ]. According to previous research, vulnerability to repeated social defeat stress is predicted by differences in IL-6 levels in the innate peripheral immune system [ 112 ]. Following induction of social defeat stress, two thirds of mice were reported to show depression-like behavior measured by social avoidance, anhedonia, circadian system disruptions, and metabolic changes [ 113 ] together with elevated activation of pro-inflammatory cytokines such as IL-6 [ 112 ]. Indeed, higher degrees of elevation in peripheral IL-6 levels of susceptible mice were reported in comparison with resilient mice. Moreover, it was found that this increase occurs within 20 min of the first social defeat. Interestingly, mice that later became susceptible had higher number of leukocytes and those leukocytes produced more levels of IL-6 following stimulation via LPS ex vivo [ 112 ]. Additionally, studies with non-social stress-based models found evidence for the functional role of IL-6 in the development of stress susceptibility. In these models, animals were exposed to a controllable or uncontrollable stress (e.g., shock), and their ability to actively escape a subsequent stressor was measured. According to the results, 20% of animals who were exposed to uncontrollable stress were found susceptible and developed learned helplessness and the rest were found to be resilient. Interestingly, susceptible animals showed elevated levels of peripheral IL-6 together with anhedonia in contrast to resilient animals [ 114 ].

Clinical studies have also revealed that patients with MDD have increased levels of plasma and serum concentrations of pro-inflammatory cytokines including IL-6 in comparison with healthy controls [ 24 , 100 , 115 , 116 ]. It should be noted that three meta-analyses verified increased peripheral IL-6 levels in MDD patients compared to healthy volunteers [ 38 , 116 , 117 ]. Nevertheless, there are also studies reporting no significant differences in IL-6 levels in MDD patients compared to healthy volunteers [ 118 ]. However, one may argue that different subtypes of depression and certain depressive symptoms should be taken into account. For instance, Rudolf et al. (2014) compared IL-6 levels among patients with atypical and typical depression and healthy controls. According to their results, IL-6 levels were significantly increased in patients with atypical depression and not in typical MDD patients compared to healthy controls [ 119 ]. Additionally, Rush et al. (2016) studied peripheral levels of IL-6 and TGF-β in 55 melancholic depressed patients. They were found to have significantly higher baseline IL-6 levels compared to healthy controls. Moreover, these elevated levels of IL-6 did not normalize following electroconvulsive therapy (ECT) [ 120 ]. A recent systematic review conformed Rush et al.’s results. In the mentioned review, authors found that peripheral IL-6 levels are increased in patients with melancholic depression in comparison with controls [ 121 ]. Moreover, Maes et al. (1997) examined serum levels of IL-6 and IL-1 receptor antagonist in patients with chronic, treatment resistant depression both before and after subchronic treatment with anti-depressants. According to their results, subchronic treatment with anti-depressants had no significant impact on serum levels of IL-6; nevertheless, it decreased serum soluble IL-6R levels significantly [ 122 ].

Effects of IL-6 on neurotransmitters’ synthesis, signaling, metabolism, and function

The effects of cytokines on neurotransmitters have been studied extensively [ 49 , 123 ]. Cytokines and their signaling pathways (e.g., p38 mitogen activated protein kinase) are reported to exhibit significant impacts on metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate; thus, influencing their synthesis, release, and reuptake [ 49 ]. Indeed, cytokines can decrease synthesis of serotonin via activating the enzyme indoleamine 2,3 dioxygenase (IDO) which breaks the precursor of serotonin (i.e., tryptophan) to kynurenine (KYN) instead of metabolizing tryptophan to serotonin; thus, leading to serotonin depletion [ 3 ]. The process of serotonin depletion has been long associated with major depression [ 124 , 125 ]. Moreover, cytokines can modulate serotonin signaling via elevating the expression and function of monoamine transporters. These transporters are known to re-uptake serotonin [ 126 , 127 ].

IL-6 is known to influence neurotransmission by modulating the behavioral output of the brain; however, the exact mechanism is unknown. A previous study showed that IL-6 directly controls the levels of serotonin transporter (SERT) and therefore influences serotonin reuptake. Indeed, the researchers concluded that IL6-induced modulation of serotonergic neurotransmission through the signal transducer and activator of transcription 3 (STAT3) signaling pathway contributes to the role of IL6 in depression [ 128 ]. The activity of SERT forms serotonergic transmission which is implicated in depressive behavioral changes and pathophysiology of the disease [ 129 ]. By intensifying dopaminergic and serotonergic turnover in hippocampus and frontal cortex, IL-6 influences neurotransmission of catecholamines [ 130 ]. It seems that noradrenaline is not affected by IL-6; however, noradrenaline itself can induce expression of IL-6 in glial cells [ 131 ]. IL-6 together with other pro-inflammatory cytokines can activate kinurenine pathway which is involved in glutamatergic neurotransmission [ 132 ].

Effects of IL-6 levels on brain morphology in depression

Previous studies showed that elevated levels of pro-inflammatory cytokines such as IL-6 may affect neurogenesis [ 133 ] and neural plasticity [ 134 ]. Imaging studies have shown that specific brain regions such as basal ganglia (which is involved in motor activity and motivation), the dorsal anterior cingulate cortex (ACC) (which has a central role in generation of anxiety), and the subgenual ACC (which is known to be involved in the development of depression) are influenced by cytokines [ 135 , 136 ]. Additionally, high IL-6 expression levels demonstrated neuropathologic manifestations including neurodegeneration [ 137 , 138 ].

There are many studies in which positron emission tomography (PET) has been applied to test translocator protein (TSPO) binding, a marker of neuroinflammation, in order to study neuroinflammatory hypothesis of depression [ 139 , 140 , 141 , 142 , 143 ]. According to their results, neuroinflammation was present in various regions of the brain (e.g., neocortical grey matter, frontal cortex, prefrontal cortex, anterior cingulate cortex, insula, temporal cortex) as well as the hippocampus [ 139 , 140 , 141 , 142 , 143 ].

In a recent study, Kakeda et al. (2018) evaluated possible relationship between serum levels of IL-1β, IL-6, IFN-γ, and TNFα and brain morphology in terms of brain cortical thinning and hippocampal subfield volumes during the first depressive episode in drug-naïve patients with MDD using a whole-brain SBM analysis. They found a significant inverse correlation between prefrontal cortex (PFC) thickness and serum IL-6 level in MDD patients. Indeed, high serum levels of IL-6 were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes in MDD patients. Additionally, thickness of the superior frontal and medial orbitofrontal cortices in patients with depression was significantly decreased compared to healthy controls. Since PFC contains high concentrations of IL-6 receptors, IL-6 mediated neurotoxicity might happen under conditions in which high serum IL-6 levels are present (i.e., early stages of MDD). Consequently, the authors advocated that the neuroinflammatory status in the early stage of MDD is associated with changes in the brain gray matter and IL-6 probably plays a key role in the morphological changes observed in the PFC during early stages of the disease. It is also noteworthy that serum IL-6 was the only cytokine among the tested cytokines that showed significant differences between the patients and controls in their study. Indeed, serum IL-6 levels were found to be significantly higher in MDD patients than in healthy controls [ 144 ]. In another study, Frodl et al. (2012) investigated possible effects of changes in the glucocorticoid and inflammatory systems on hippocampal volumes in patients with MDD. According to their results, MDD patients showed increased IL-6 levels and smaller hippocampal volumes compared to healthy controls. Positive effects of messenger RNA (mRNA) expression of glucocorticoid-inducible genes and further inverse effects of IL-6 concentration, on hippocampal volumes were also reported. Thus, they concluded that increased expression of IL-6 can probably predict decreased hippocampal volume [ 145 ].

As already mentioned, there is considerable amount of evidence regarding the central role of the highly plastic, stress-sensitive hippocampal region in pathogenesis of depression [ 146 ]. Indeed, grey-matter structures, including the hippocampus are vulnerable to atrophy in depression [ 147 , 148 ]. Hippocampal volume reductions are most probably the result of remodeling of key cellular elements, involving retraction of dendrites, loss of glial cells, and decreased neurogenesis in the dentate gyros [ 149 ]. Factors underlying this cellular remodeling are known to be stress-induced increased levels of glucocorticoids, which are implicated in decreased neurogenesis [ 150 ]. Moreover, increased activity of the HPA axis resulting in decreased levels of glucocorticoids combined with resistance to glucocorticoid-induced negative feedback control is commonly observed in depression [ 151 ]. This dysregulation of glucocorticoid secretion along with the increased activity of excitatory neurotransmitters can potentially lead to cellular remodeling (which can be reversible) and hippocampal neurons cell death in patients with depression [ 152 ]. Since hippocampus has been identified to have a role in negative feedback inhibition of glucocorticoids, remodeling or neuronal damage may lead to less efficient inhibitory control of the corticotrophin-releasing hormone, resulting in elevated amounts of circulating glucocorticoids and further damage of the hippocampal neurons [ 153 ]. Taken together, it seems that further studies are required to elucidate the physiological mechanisms in which IL-6 might exert changes in the brain grey matter. A brief overview of the effects of cytokines including IL-6 on brain morphology is shown in Fig. 1 .

Effects of cytokines including IL-6 on brain morphology

Blockade of IL-6 and its receptor in the periphery as a potential therapeutic option in MDD

Growing body of evidence suggests that abnormalities in the immune system are most probably relevant to pathogenesis and potential novel treatment of psychiatric disorders. Previous studies showed that alterations in the peripheral IL-6 levels might contribute to depressive-like behavior in animal studies [ 3 , 112 , 114 , 154 ]. Moreover, IL-6 knockout mice showed resistance to development of depressive-like behavior [ 155 ] which gives further evidence for possible role of IL-6 pathogenesis of depression. High peripheral levels of IL-6 are even more apparent in patients with treatment-resistant depression. Additionally, correlations have been found between decrease in IL-6 levels and alleviation of depressive symptoms in patients who were responsive to the pharmacotherapy [ 156 ]. Moreover, results of a study on 222 stroke patients indicated significant associations between IL-6 periphery levels and development of MDD within 2 weeks and at 1 year following stroke. Furthermore, significant correlations were found between statin use and IL-6 on the presence of a depressive disorder at the 1st year. Indeed, preventive effects of treatment with statins (which are known to possess anti-inflammatory properties and potently reduce the cytokine-mediated IL-6 release [ 157 ]) against post-stroke depression was confirmed [ 158 ]. Thus, suppression of IL-6 activity could possibly lead to clinical recovery and may be considered as a novel pharmacotherapeutic option. Utilizing IL-6 receptor antibodies (for instance, Tocilizumab) or IL-6 antibodies (for instance, Sirukumab or Siltuximab) for reduction of IL-6 activity seems to be a novel strategy.

Blockade of IL-6 receptor by the humanized anti-IL-6 antibody, Tocilizumab has been used in treatment of rheumatoid arthritis (RA) [ 159 , 160 , 161 , 162 , 163 ] and systemic juvenile idiopathic arthritis [ 164 , 165 , 166 ]. Extensive clinical studies have established both short-term and long-term efficacy and safety of Tocilizumab [±conventional disease-modifying anti-rheumatic drugs (DMARDs)] in adults with moderate to severe RA. Additionally, Tocilizumab was shown to be effective as a monotherapy in patients with systemic juvenile idiopathic arthritis and also in patients whose disease has been refractory to other therapies [ 164 ]. Moreover, the safety profile of tocilizumab was reported to be consistent over time and also consistent with safety profile of other immunomodulatory agents [ 162 ]. It is also important to note that oral tocilizumab has been shown to inhibit experimental autoimmune encephalitis by elevating Th2 anti-inflammatory cytokines and decreasing pro-inflammatory Th1 cytokines [ 167 ]. With regard to crucial role of IL-6 in regulating metabolic homeostasis, side effects such as significant weight gain followed by hypertrygliceridemia and hypercholesterolemia may be observed in patients treated with tocilizumab [ 168 ]. Blockade of IL-6 trans-signaling, while classical IL-6R signaling stays intact seems to be crucial for the goal of maintaining gut mucosal integrity and epithelial regeneration [ 65 ]. Indeed, few randomized clinical trials were conducted on anti-depressant properties of tocilizumab. According to the results of a recent meta-analysis of anti-depressant activity of anti-cytokine therapies, treatment with tocilizumab showed statistically significant improvements in depressive symptoms [ 169 ].

Another promising human monoclonal antibody against Il-6, namely Sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in patients with inflammatory disorders (e.g., rheumatoid arthritis). It targets the IL-6 signaling pathway by inhibition of both the pro- and anti-inflammatory effects of IL-6 [ 170 ]. Effects of Sirukumab on cytokine networks provide a well-founded rationale for its potential use in pharmacotherapy of psychiatric disorders promising possible advantages across varying domains of the biobehavioral research criteria [ 171 ]. In a phase 2, double-blind, placebo-controlled trial, the efficacy of Sirukumab and Siltuximab on depressive symptoms was studied in patients with rheumatoid arthritis or multicentric Castleman’s disease respectively. Compared with placebo, both IL-6 neutralizing antibodies were found to make significantly greater improvements on depressive symptoms in the patients [ 172 ]. Results of a recent mega-analysis of 18 randomized, placebo-controlled clinical trials of efficacy of immunomodulatory drugs on depressive symptoms in patients with inflammatory disorders demonstrated promising results ( N = 10,743 participants). According to their findings, anti-IL-6 antibodies (sirukumab and siltuximab) had large and statistically significant effect sizes on core depressive symptoms before correction for physical health outcomes. Additionally, their effects remained significant in non-responders for the primary disease states evaluated [ 173 ]. Although further research is needed in this area, potential application of anti-IL-6 antibodies could possibly open new avenues in pharmacotherapy of MDD.

Possible role of IL-6 together with gut microbiota in pathogenesis of depression

The human intestine harbors nearly 100 trillion bacteria [ 174 ] consisting assemblages of microorganisms associated with various niches in and on the body with long-term implications to health [ 175 ]. Evidence is emerging regarding correlations of microbial activities with progressive structural and functional processes in the brain of both animal models and humans [ 175 ]. There is a large body of evidence for the role of gut microbiota composition in pathogenesis of depression [ 176 , 177 , 178 , 179 , 180 ]. Moreover, there is growing body of literature for the influence of the gut microbiome on cytokine signaling [ 181 , 182 ].

The dominant gut microbial phyla are known to be Firmicutes and Bacteroideteds [ 183 , 184 ]. The Firmicutes / Bacteroideteds ratio is of great relevance in signaling human gut microbiota status [ 185 ]. For instance, increased levels of Firmicutes / Bacteroideteds ratio have been reported in patients suffering from irritable bowel syndrome (IBD) and seem to have some correlations with development of depression and anxiety [ 186 , 187 ]. Additionally, Firmicutes / Bacteroideteds ratio is associated with overall alterations in bacterial profiles at different life stages [ 185 ]. In a novel study, researchers reported decreased Firmicutes / Bacteroideteds ratio in mice following social defeat stress; thus, proposing possible role of Firmicutes / Bacteroideteds in depressive-like behavior. Furthermore, administration of anti-mouse IL-6 receptor antibody (MR16-1) attenuated the decreased ratio of Firmicutes / Bacteroideteds in susceptible mice. Thus, the researchers concluded that anti-mouse IL-6 receptor antibody may have anti-depressant-like effects by normalizing the Firmicutes / Bacteroideteds ratio via modulation of the immune system [ 3 ].

Decreased number of Oscillospira was detected in patients with depression [ 180 ] which suggests for possible role of Oscillospira in pathogenesis of depression. Two animal studies yielded same results. A recent study investigated therapeutic effects of finasteride on depressive-like behavior in rats together with 1 month of treatment withdrawal. Withdrawal from finasteride was associated with increased depressive-like behavioral responses. Therapeutic use of finasteride was linked with elevations in the phylum Bacteroidetes and in the family Prevotellaceae, and withdrawal was found to be correlated with decreases in the family Ruminococcaceae and the genera Oscillospira and Lachnospira [ 188 ]. In another study, socially stressed mice developing depression-like symptoms showed increases at the genus level of fecal Oscillospira . Interestingly, IV administration of anti-mouse IL-6 receptor antibody (MR16-1) normalized depression-like behavior and resulted in significant decrease in Oscillospira levels towards pre-stressor levels [ 3 ]. Moreover, increased number of Sutterella was reported in fecal samples [ 189 ] and intestinal biopsy samples of children with Autism spectrum disorder [ 190 ]. Additionally, elevated number of Staphylococcus and Sutterella were found in mice following social defeat stress. It is likely that Staphylococcus and Sutterella play a role in the depressive-like behavior via infection-induced inflammation. Interestingly, administration of anti-mouse IL-6 receptor antibody resulted in attenuation of elevated number of Staphylococcus and Sutterella following social defeat stress in mice [ 3 ].

These findings advocate that peripheral IL-6 may have a significant role in pathogenesis of MDD and blockade of IL-6 receptor in the periphery may exhibit rapid-onset effects by attenuating the altered composition of gut microbiota. Taking into account the role of gut-microbiota in immunomodulation, it is highly probable that gut-microbiota-brain- axis plays a role in anti-depressant actions of treatment with anti-IL-6 receptor [ 3 ]. A brief overview of the role of IL-6 together with gut microbiota in pathogenesis of depression is shown in Fig. 2 .

A brief overview of the role of IL-6 together with gut microbiota in pathogenesis of depression

Elevated levels of IL-6 in patients with COVID-19 infection

The world-wide effect of the coronavirus disease 2019 (COVID-19) pandemic is enormous and is not solely limited to the increased mortality and morbidity rates, but also extends into the mental health of the global population [ 191 ]. Considerable amount of clinical data is emerging regarding the manifestation of depression in patients during [ 192 , 193 , 194 ] and post-COVID 19 infection [ 192 , 193 , 194 , 195 ]. It is estimated that about 48% of confirmed COVID-19 cases displayed overt psychological symptoms such as depression and often expressed feelings of regret, loneliness, helplessness, and irritation [ 196 ].

There is growing body of literature regarding dual role of IL-6 in COVID-19 infection and depression [ 192 ]. Normal plasma levels of IL-6 in adults range between 1 and 10 pg/ml; whereas in a systemic inflammation this amount increases to several ng/ml [ 197 ] and even higher concentrations were reported in COVID-19 patients [ 198 ]. Indeed, cytokine release syndrome (CRS) is common in COVID-19 patients and increased levels of serum IL-6 have been identified to be significantly associated with acute respiratory distress syndrome (ARDS), respiratory failure, and poor disease outcome in numerous studies [ 192 , 199 , 200 , 201 ]. Studies suggest that new onset depression is most probably caused by inflammation initiated during the active phase of the infection leading to a cytokine surge [ 202 ]. Indeed, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects primarily human monocytes and dendritic cells causing dendritic cell dysfunction, leading to T cell apoptosis and exhaustion; thus, contributing to the immunopathology [ 203 ]. Alpert et al. (2020) described two cases of COVID-19 patients with elevated amounts of IL-6 (25 pg/mL and 26.7 pg/mL respectively) who were diagnosed with major depressive disorder (according to the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5)) during COVID 19 infection. Both patients’ depressive symptoms subsided about 6 weeks after initiation of anti-depressant pharmacotherapy and normalization of the inflammatory cytokines [ 192 ]. The authors concluded that lower cytokine activity ameliorates depressive symptoms as normalization of IL-6 plasma levels decreased depression with or without anti-depressants [ 192 ]. Moreover, Benedett et al. (2020) studied effects of treatment with cytokine-blocking agents on the psychopathological status of the patients with COVID-19 infection. Their results were in favor of the protective effects of treatment with cytokine-blocking agents in early phases of COVID-19 against the later onset of depression [ 204 ].

It is indeed crucial to maintain a multidisciplinary approach in management of the psychological effects of this debilitating pandemic. Treatment strategies addressing the immunopathology of SARS-CoV-2 infection will be promising during the acute phase of the disease [ 192 , 205 ]. Currently, there are few studies considering psychological and neuropsychiatric implications of COVID-19; however, it is very likely to expect an increased incidence of mental pathologies both during and post-COVID-19 infection.

Preclinical and clinical studies present strong evidence that inflammation is altered in a subset of patients with MDD and there is mounting body of literature for the role of pro-inflammatory cytokines namely IL-6 in pathophysiology of depression. Nevertheless, there still exists gap in our understanding of the mechanisms by which IL-6 signaling and its molecular components could possibly contribute to depression manifestation. A number of humanized monoclonal antibodies are undergoing clinical trials for potential pharmacotherapy of mood disorders. Biologics including IL-6 receptor antibodies or IL-6 antibodies are currently approved to treat inflammatory disorders such as RA and are undergoing clinical trials as a novel target for MDD treatment. However, these novel therapeutic targets may also raise the possibility of potential side effects. By investigating the interface of peripheral cytokines, namely IL-6 and brain cellular processes contributing to depression, one might be able to develop novel therapeutic options for treatment of mood disorders by sequestering and preventing this peripherally derived inflammatory marker from acting upon mood circuits in the CNS. In sum, therapeutic deficiency in treatment outcomes reflects the growing demand for revitalizing psychiatric therapeutics with novel options that could potentially open new avenues in treatment of this debilitating disorder and enhancement of patients’ quality of life.

Availability of data and materials

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Abbreviations

Anterior cingulate cortex

Acute respiratory distress syndrome

Blood-brain barrier

Central nervous system

Coronavirus disease 2019

Cytokine release syndrome

Conserved transcriptional response to adversity

Disease-modifying anti-rheumatic drugs

Diagnostic and Statistical Manual of Mental Disorder, 5th Edition

Electroconvulsive therapy

Glycoprotein 130

G-protein-coupled receptors

Hypothalamic-pituitary-adrenal

Indoleamine 2,3 dioxygenase

Interleukin

IL-6 receptor

Janus kinase/signal transducer and activator of transcription

• Major depressive disorder

Mitogen-activated protein kinase

Messenger RNA

Nuclear factor kappa-light-chain-enhancer of activated B cells

Prefrontal cortex

Rheumatoid arthritis

severe acute respiratory syndrome coronavirus 2

Serotonin transporter

Signal transducer and activator of transcription 3

Soluble IL-6R

Transforming growth factor

T helper type 2

T helper type 1

T helper cell

Tumor necrosis factor

Translocator protein

Regulatory T cells

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Roohi, E., Jaafari, N. & Hashemian, F. On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?. J Neuroinflammation 18 , 45 (2021). https://doi.org/10.1186/s12974-021-02100-7

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Mini review article, neuroinflammatory basis of depression: learning from experimental models.

• 1 BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea
• 2 Brain Science and Engineering Institute, Kyungpook National University, Daegu, South Korea

The neuroinflammatory basis of depression encompasses the detrimental role of otherwise supportive non-neuronal cells and neuroinflammation in hampering neuronal function, leading to depressive behavior. Animals subjected to different stress paradigms show glial cell activation and a surge in proinflammatory cytokines in various brain regions. The concept of sterile inflammation observed in animal models of depression has intrigued many researchers to determine the possible triggers of central immune cell activation. Notably, microglial activation and subsequent phenotypic polarization in depression have been strongly advocated by the wealth of recent preclinical studies; however, findings from human studies have shown contradictory results. Despite intensive investigation, many research gaps still exist to elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression. In this mini-review, recent progress in understanding neuroinflammatory mechanisms in light of experimental models of depression will be thoroughly discussed. The challenges of mirroring depression in animal and in vitro models will also be highlighted. Furthermore, prospects of targeting neuroinflammation to treat depressive disorder will be covered.

Introduction

Major depressive disorder (MDD) is the most prevalent debilitating psychiatric disorder affecting individuals during some part of their life, resulting in a substantial health and economic burden worldwide ( Konig et al., 2019 ; Konnopka and Konig, 2020 ). Neurochemical and structural alterations in mesolimbic and corticolimbic neural circuitry that regulate mood and behavior, including the prefrontal cortex (PFC), amygdala, nucleus accumbens, and hippocampus, are reported to be the cause of depression symptoms ( Duman et al., 2016 ). Dysregulation of monoaminergic neurotransmission, including serotonin and dopamine, is a widely accepted theory of depression pathology, and various perturbations in monoamine signaling and metabolism have been identified ( Jesulola et al., 2018 ). Moreover, deficits in synaptic plasticity induced by altered glutamatergic neurotransmission are involved in depression pathology, constituting the “neuroplasticity” hypothesis of depression ( Pittenger and Duman, 2008 ). Various drugs interfering with glutamatergic neurotransmission have been reported to exert antidepressant actions in clinical and preclinical studies ( Pittenger and Duman, 2008 ). Brain-derived neurotrophic factor (BDNF) is known to play an important role in neuroplasticity, and decreased BDNF expression has been reported in various brain regions of depressed patients ( Dwivedi, 2009 ). All of these mechanisms play a crucial role in the pathology of depression; however, the inefficacy of antidepressant drugs in a subpopulation of patients with MDD and decreased remission rates highlight the involvement of diverse mechanisms in addition to these neurocentric theories.

Emerging evidence provides ample support for the involvement of non-neuronal cells leading to a neuroin-flammatory milieu in depression neurobiology ( Koo and Duman, 2008 ; Steiner et al., 2011 ; Strawbridge et al., 2015 ). Glial cells constitute a major proportion of brain tissue and play a significant role in maintaining brain homeostasis by supporting neurons in dynamic ways. Increased microglial inflammatory activation, astrocytic atrophy, and decreased myelin basic protein immunoreactivity and fewer mature oligodendrocytes have been documented in MDD subjects and animal models of depression ( Cotter et al., 2001 ; Tynan et al., 2013 ; Yang et al., 2015 ). The inflammatory activation of microglial cells has been reported to alter glutamatergic neurotransmission, impair monoamine synthesis, and interfere with BDNF signaling, culminating in altered synaptic plasticity and neurogenesis, and precipitating depression ( Weber et al., 2019 ).

Neuroinflammatory perturbations identified in animal models of depression provide a strong basis for non-neuronal cell involvement in MDD pathology ( Weber et al., 2017 ; Wang et al., 2018 ). Several in vitro experimental models of MDD, which provide cell-level information, have been developed to enhance the usefulness of in vivo models ( Zunszain et al., 2012 ; Zhang et al., 2020b ). All these models are of value for deciphering the fundamental mechanisms underlying MDD pathology and testing novel therapies targeted against this disease. In this review, recent literature documenting neuroinflammatory alterations observed in experimental models of depression is discussed. Subsequently, plausible reasons behind discrepancies between data from human studies and preclinical data are highlighted. Additionally, the therapeutic significance of targeting neuroinflammation in depressive disorders will be discussed.

Neuroinflammation in the Pathophysiology of Depression

Environmental and genetic factors have been identified as crucial drivers of depression pathology in both human and rodent models ( Lesch, 2004 ; Levinson, 2006 ). As these factors are highly variable, epistatic, and complex, they are thought to regulate vulnerability to depression development and responsiveness to antidepressant therapy. Various polymorphisms have been reported in genes regulating the hypothalamic–pituitary–adrenal (HPA) axis, serotonin recycling, and immune responses, including corticotropin-releasing hormone receptor 1, the sodium-dependent serotonin transporter gene ( SLC6A4 ), and interleukin-1β (IL-1β) ( Baune et al., 2010 ; Schiele et al., 2021 ). Moreover, environmental stressors are associated with epigenetic modification of BDNF, its receptor tropomyosin-related kinase B gene, glucocorticoid receptor gene ( NR3C1 ), and glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) ( Ernst et al., 2009 ; Jiang et al., 2010 ; Sun et al., 2013 ; Efstathopoulos et al., 2018 ).

Accumulating evidence suggests the involvement of multiple biological systems, including the neuroendocrine system, immune system, and neural circuitry, in the pathophysiology of depression ( de Kloet et al., 2005 ). Activation of the HPA axis results in increased cortisol secretion in the blood, which in turn activates peripheral immune cells ( Otte et al., 2016 ). Inflammatory signals from peripheral immune cells are propagated through various humoral, neural, and cellular pathways and results in the activation of brain resident immune cells that interfere with neurotransmitters and directly affect neuronal integrity through excitotoxicity.

Triggers and Mediators of Neuroinflammation in Depression

The activation of the HPA axis and sympathetic system is an adaptive response of an organism toward any psychological or environmental stimuli perceived as a threat, resulting in the release of glucocorticoids (GC) and norepinephrine (NE) in the blood ( Selye, 1976 ; McEwen et al., 2016 ). Increased GC and sympathetic signaling exert proinflammatory effects by mobilizing immune cells from the bone marrow, lymph node, and spleen and increasing their inflammatory activation ( Engler et al., 2004 ; Dhabhar et al., 2012 ; Powell et al., 2013 ). Inflammatory activation of monocytes and macrophages leads to increased secretion of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), IL-1β, and interleukin-6 (IL-6) ( Serrats et al., 2010 ). Increased proinflammatory cytokines in circulation also have the propensity to repress the expression of several tight-junction proteins of the blood–brain barrier (BBB), including claudin-5 ( Dudek et al., 2020 ). Mice exposed to chronic social defeat stress (CSDS) exhibited decreased expression of claudin-5, positively correlating with heightened peripheral TNF-α in circulation ( Dudek et al., 2020 ). Chronic stress-induced BBB leakage in an animal model of depression allows the passage of proinflammatory mediators ( Menard et al., 2017 ).

Recent literature also highlights the potential role of gut microbiome in precipitating inflammatory signals in depression pathology. Among divergent pathways through which gut microbiota can alter behavior, leading to depressive-like outcomes, is an inflammation-to-brain mechanism ( Guo et al., 2019 ). A study in rodents demonstrated the activation of the master regulator of the inflammatory pathway nuclear factor-κB (NF-κB) when gut microbiota was altered by chronic restraint stress (CRS). The depletion of Lactobacillus was accompanied by increased inflammatory cytokines as well as increased microglial activation in the hippocampus ( Guo et al., 2019 ). Although the mechanism of immune cell activation was not investigated, it is quite plausible that inflammatory signaling is involved, as Lactobacillus treatment reduced inflammation and alleviated depressive symptoms in mice subjected to CRS, highlighting the potential role of the gut-inflammatory pathway in exerting behavioral consequences.

Contribution of Malfunctioning Glia

Astrocytes, microglia, and oligodendrocytes are the major types of the glial population, each having a distinct role in healthy and diseased states. Accumulating evidence suggests that gliosis and inflammation lead to increased levels of proinflammatory cytokines and reactive oxygen species (ROS) in various brain regions, thereby contributing to neuronal damage and leading to altered mood and behavior. Astrocytes are the most abundant glial cells that provide metabolic and trophic support to neurons. Atrophy and reduction in number of astrocytes as well as a reduction in various astrocytic proteins have been documented in MDD pathology ( Fatemi et al., 2004 ; Zhao et al., 2018 ). Reduced astrocyte numbers in the hippocampus, amygdala, and prefrontal cortex of MDD patients have been reported ( Altshuler et al., 2010 ; Cobb et al., 2016 ). The excitotoxicity observed in MDD can be correlated with astrocytic dysfunction. The inability of astrocytes to uptake glutamate from the synaptic cleft leads to prolonged synaptic activation, which in turn leads to excitotoxicity ( Choudary et al., 2005 ).

Microglia are highly plastic, brain resident macrophages, that mainly guard the brain parenchyma in addition to playing other physiological roles. Microglia display extensive phenotypic plasticity dependent on surrounding cues. Recent studies suggest the important role of stress-induced damage-associated molecular patterns as a primary signal in activating microglia. The primed state of microglia that is characterized by an increased expression of proinflammatory cytokines increases the propensity for the development of severe depressive symptoms ( Wohleb et al., 2014 ). In the CSDS model, it has been reported that microglia-secreted proinflammatory cytokines are crucial for the recruitment of peripheral immune cells in stress-responsive brain regions, and these cells remain sensitized for a longer period after cessation of the acute stressful stimuli ( Wohleb et al., 2014 ). In addition, the study provided useful insights into the temporal effects of stress on the neuroimmune axis ( Wohleb et al., 2014 ). A surge in proinflammatory cytokines due to microglial activation and peripheral immune cell infiltration leads to the upregulation of microglial indolamine 2,3 dioxygenase (IDO) activity ( Corona et al., 2013 ). Increased microglial IDO activity diverts tryptophan metabolism from serotonin to quinolinic acid (QUIN), which is a N-methyl-D aspartate receptor agonist, serving as a link between immune and neurotransmitter changes in depression. Increased inflammatory cytokines, including TNF-α, in microglial cells can also influence the neuronal re-uptake of monoamine neurotransmitters by regulating neuronal mitogen-activated protein kinase (MAPK), leading to an increased surface expression of monoamine transporters on neurons ( Zhu et al., 2010 ). Cytokine-mediated increases in microglial QUIN and reduction in astrocytic glutamate uptake can lead to excessive glutamate levels and actions, thereby altering synaptic plasticity.

Experimental Models of Depression

With advances in our understanding of molecular mechanisms of depression, efforts have been made to establish in vivo and in vitro models that can be used efficiently for a better understanding of the enigmatic pathophysiology of depression. Although still not completely achieved, few experimental models, including in vivo and in vitro , have been used frequently in neuroscience research.

In vivo Models of Depression

Considering stress as a major factor in predisposing humans to the development of depression, most animal models used in preclinical studies are based on stress. Though many of these models lack etiological relevance, the hyperactive HPA axis, impaired neuroplasticity and neurogenesis, and altered neurotransmitters are consistent features of these models that can be paralleled with human depression disease. Thus, the contribution of these models in providing novel insights into depression pathology cannot be underscored. Specifically, the role of neuroinflammation in the pathophysiology of depression has been well-established in these models and explains the antidepressant action of certain anti-inflammatory drugs ( Table 1 ).

Table 1. Neuroinflammatory markers in animal models of depression.

CSDS, chronic unpredictable mild stress (CUMS), and CRS are the most widely employed animal models to decipher the neuropathological basis of depression. Increased neuroinflammatory profile characterized by elevated cytokines and the C-C Motif Chemokine ligand 2 (CCL2), and reduced anti-inflammatory regulation of neuronal-derived fractalkine ligand (CX3CL1) and microglial receptor (CX3CR1) are shared features in these models ( Wohleb et al., 2014 ; Ramirez et al., 2016 ). Increased proliferation of inflammatory microglia with concomitant increase of Iba-1 immunoreactivity in the hippocampal tissue of mice subjected to CRS and CUMS has been reported ( Feng et al., 2019 ; Horchar and Wohleb, 2019 ). Mice subjected to CSDS stress also exhibited microglial activation, recruitment of peripheral macrophages into the brain, and anxiety-like behavior ( Tang et al., 2018 ). Inflammatory activation of microglia, stimulation of the microglial NLRP [NLR (nucleotide-binding domain and leucine-rich repeat) family, pyrin domain containing] inflammasome, and increased IL-1β production in the PFC were demonstrated in CUMS ( Pan et al., 2014 ). Microglia isolated from mice subjected to CSDS have gene ontology profiles signifying increased inflammation, phagocytosis, and ROS production ( Lehmann et al., 2018 ). The behavioral phenotypes observed in these models, including anhedonia, decreased sociability, and despair, are positively correlated with inflammatory activation of microglia.

Deficits in synaptic plasticity, altered dendritic spine density, and impaired neurogenesis because of heightened neuroinflammation have been reported in CSDS, CRS, and CUMS. Increased caspase-1 signaling in hippocampal region of mice after CSDS, CRS, and CUMS leads to dysregulated glutamatergic neurotransmission accompanied by altered dendritic spine density and reduced synaptic plasticity ( Li et al., 2018 ). The genetic and pharmacological targeting of the IL-1β-caspase-1 pathway rescued the development of depressive behaviors in mice, highlighting the crucial role of neuroinflammatory pathways in impairing neuronal integrity ( Li et al., 2018 ). Microglia-derived IL-1 can exert its detrimental effects on neurogenesis indirectly by stimulating the HPA axis as well as directly by activating IL-1 receptors expressed on hippocampal neural progenitor cells, resulting in decreased cell proliferation that is mediated by the NF-κB signaling pathway ( Koo and Duman, 2008 ). Hence, microglial inflammatory activation as well as the neuroinflammatory milieu in animal models of depression may play key roles in the pathophysiology of depression.

In vitro Models of Depression

Depression research is hampered by the absence of in vitro models that can recapitulate all molecular mechanisms of the disease. Attempts to model depression in vitro using hippocampal progenitor cell lines (HPCs) to study the pathways causing impaired neurogenesis are emerging. Thus far, studies have focused on isolated cell types in culture or occasionally two cell types in co-culture, which cannot fully model the important contributions of various cell types in disease. Various depressogenic stimuli identified in clinical and preclinical studies are used to study the mechanism or unravel pharmacological targets in neuronal cells and glial cell cultures ( Table 2 ). Neurogenesis in the hippocampus regulates the HPA axis via a negative feedback mechanism; hence, the mechanisms underlying impairments in adult hippocampal neurogenesis have been explored in vitro ( Schloesser et al., 2009 ). Microglia isolated from the hippocampus of cytokine-induced depressed mice suppressed neural stem/precursor cell proliferation and stimulated apoptosis of immature neurons, highlighting the role of microglia in impairing neurogenesis in depression pathology ( Zhang et al., 2020a ). IL-1β inhibited neurogenesis in HPCs by activating the neurotoxic branch of the kynurenine pathway, which has been postulated to be involved in the development of depressive disorders ( Zunszain et al., 2012 ).

Table 2. Experimental findings in in vitro model of depression.

Findings in Human Depression Studies

Although increased levels of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, in the plasma and CSF of depressed patients, have been reported, there still lies a big question mark on neuroinflammatory markers and microglial activation status ( Martinez et al., 2012 ; Himmerich et al., 2019 ). The elevated translocator protein (TSPO) binding assessed by positron emission tomography studies in various brain regions of depressed patients backs microglial activation ( Setiawan et al., 2015 ; Owen et al., 2017 ). Also, studies using other markers of microglial activation, such as Iba-1 or quinolinic acid, have found increased microglial reactivity in depression, whereas no difference between the density of major histocompatibility complex (HLA)-immunoreactive microglia in post-mortem brain samples of depressed subjects ( Hamidi et al., 2004 ; Snijders et al., 2020 ). A recent study using single-cell high-dimensional mass cytometry (CyTOF) examined microglia from post-mortem MDD samples from different brain regions and found increased markers of homeostatic microglia, including transmembrane protein (TMEM)119 and P2Y12 in MDD compared to controls, which is in clear contrast with what has been found in animal studies ( Bottcher et al., 2020 ). Gene expression analysis of microglia isolated from animal models of depression clearly showed enhanced inflammatory markers, including CD11b, CD45, and TLR4 ( Wohleb et al., 2011 ; Lehmann et al., 2016 ). Moreover, gene expression profiling of post-mortem frontal lobe tissue from patients with MDD did not show any difference in the expression of IL-6 or TNF-α ( Shelton et al., 2011 ). Furthermore, no differential expression of IL-6, IL-1β, or TNF-α mRNAs was found in post-mortem brain tissue of MDD cases ( Bottcher et al., 2020 ).

It is not possible to mimic all the pathological features of human depression in animal models, owing to its multifactorial pathology involving epigenetic and genetic factors, multiple body systems working in conjunction, and subjectivity of symptoms. Yet, these models have provided useful insights into the neuroinflammatory mechanism of depression. Given that the role of neuroinflammation in human depression is yet not clear, the results of in vivo depression studies appear to be missing pieces of the puzzle of depression pathology ( Nettis et al., 2021 ).

Targeting Microglia and Neuroinflammation in Depression

Recent literature highlights the crucial role of brain immune cells in depression pathology and any modality that can modulate the activity of these cells or reduce neuroinflammation, thereby bearing the potential to treat depressive symptoms. Supporting this notion, beneficial effects of anti-inflammatory drugs have been observed in MDD patients ( Muller et al., 2006 ; Abbasi et al., 2012 ; Kobayashi et al., 2013 ; Majd et al., 2015 ; Cao et al., 2020 ; Nettis et al., 2021 ). Clinical trials using non-steroidal anti-inflammatory drugs in depressed patients have reported promising results, with increased remission rates in patients when used in combination with conventional antidepressant drugs ( Abbasi et al., 2012 ; Cao et al., 2020 ). A tetracycline antibiotic, minocycline, an inhibitor of microglial inflammatory activation, has also shown promising antidepressant activity in treatment-resistant depression patients ( Kobayashi et al., 2013 ; Nettis et al., 2021 ). The antidepressant effects of minocycline were independent of changes in peripheral inflammatory biomarkers, reflecting the possible decrease in central inflammation ( Nettis et al., 2021 ).

Mounting evidence also suggests the protective role of targeting neuroinflammation in in vivo models of depression. Pharmacological inhibition of caspase-1, which converts IL-1β to its mature form, alleviated the depressive phenotype in preclinical models by modulating neuroinflammatory pathways and stabilizing the surface expression of glutamate receptors ( Li et al., 2018 ). Microglial activation was inhibited by pharmacological treatment with minocycline in a variety of stress models, reducing the increase of proinflammatory cytokines ( Hinwood et al., 2012 ; Kreisel et al., 2014 ). Furthermore, minocycline attenuated stress-associated deficits in cognitive memory tasks, including the Morris water maze and Barnes maze, as well as depressive-like and anxiety-like behaviors, such as reduced social interaction, sucrose preference, and open field exploration ( Hinwood et al., 2012 ). Moreover, pharmacological inhibition of microglial ATP-gated purinergic P2X7 receptor, activation of which leads to the maturation of IL-1β, also suppressed the development of depressive behavior in rodents subjected to CUMS ( Bhattacharya et al., 2018 ). Adipose-derived mesenchymal stem cells also produced antidepressant effects by modulating microglial phenotype, suppressing TLR4/NF-κB signaling pathways, and upregulating antioxidant pathways in mice subjected to CUMS ( Huang et al., 2020 ). Anesthetic ketamine, which has antidepressant potential, is also known to suppress inflammatory pathways ( Abdallah et al., 2020 ). It has been recently demonstrated in CUMS model that ketamine suppressed microglial activation and NLRP1 inflammasome pathway, exerting antidepressant effects ( Aricioglu et al., 2020 ). These preclinical studies suggest that targeting neuroinflammation appears to be a promising therapeutic approach.

Conclusion and Prospects

Owing to complex neurobiology and genetic variability, depression cannot be fully mimicked in animal models. However, many molecular insights can be gained from these models to identify therapeutic targets for depression. The heightened role of neuroinflammatory cascades observed in animal models of depression and the efficacy of anti-inflammatory treatment in decreasing depressive behavior pinpoint the role of neuroinflammation in the neurobiology of depression. Moreover, the inefficacy of classical antidepressant drugs partly explains the unappreciated role of neuroinflammation in depressive disorders and paves a path for targeting neuroinflammation to treat depression.

Author Contributions

RA conducted the literature review, formulated, and wrote the manuscript. KS edited the manuscript and was involved in all aspects of manuscript preparation. Both authors contributed to the article and approved the submitted version.

This work was supported by a grant from the Basic Science Research Program through the National Research Foundation (NRF), which was funded by the Korean Government (Ministry of Science, ICT and Future Planning, MSIP; 2017R1A5A2015391 and 2020M3E5D9079764).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords : glia, depression, neuroinflammation, cytokines, immune cells, experimental models

Citation: Afridi R and Suk K (2021) Neuroinflammatory Basis of Depression: Learning From Experimental Models. Front. Cell. Neurosci. 15:691067. doi: 10.3389/fncel.2021.691067

Received: 05 April 2021; Accepted: 08 June 2021; Published: 02 July 2021.

Reviewed by:

Copyright © 2021 Afridi and Suk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Kyoungho Suk, [email protected]

This article is part of the Research Topic

Multifaceted interactions between immunity and the diseased brain

Inflammatory theory of depression

Affiliation.

• 1 Klinika Psychiatrii Dorosłych, Uniwersytet Medyczny w Łodzi.
• PMID: 30218560
• DOI: 10.12740/PP/76863

Brain diseases are one of the most socially and economically burdening diseases in Europe. Among all brain diseases, more than 60% of social and economic costs are generated by mental disorders (mainly depressive disorders and anxiety disorders). Recurrent depressive disorders have been a significant civilizational problem in recent times. Among the biological and psychological theories explaining the causes of depression, the hypothesis involving an active inflammatory process taking place in a human organism is becoming increasingly important. The following are considered inflammation markers: inflammatory enzymes (e.g., manganese superoxide dismutase (MnSOD), myeloperoxidase (MPO), inducible nitric oxide synthase), proinflammatory and anti-inflammatory cytokines, and the phenomenon of oxidative stress. Through the kynurenine pathway, these factors lead to a deficit in serotonin and melatonin, which is considered one of the main reasons of depression. We can consider depression to be a chronic cold of the organism, which develops in response to the action of greater or smaller everyday stressors. This paper presents results of recent studies regarding this matter.

Keywords: cognition; depression; emotions; inflammation theory.

Publication types

• Cytokines / immunology*
• Depressive Disorder / metabolism*
• Inflammation / complications*
• Inflammation / immunology
• Stress, Psychological / metabolism*

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• Published: 09 January 2023

Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression

• Bingqi Guo   ORCID: orcid.org/0000-0002-7399-2691 1 , 2 ,
• Mengyao Zhang 1 , 2 ,
• Wensi Hao 1 , 2 ,
• Yuping Wang   ORCID: orcid.org/0000-0002-6482-9710 1 , 2 , 3 ,
• Tingting Zhang   ORCID: orcid.org/0000-0003-3687-3623 1 , 2 &
• Chunyan Liu   ORCID: orcid.org/0000-0002-8063-6580 1 , 2  

Translational Psychiatry volume  13 , Article number:  5 ( 2023 ) Cite this article

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Mood disorders are associated with elevated inflammation, and the reduction of symptoms after multiple treatments is often accompanied by pro-inflammation restoration. A variety of neuromodulation techniques that regulate regional brain activities have been used to treat refractory mood disorders. However, their efficacy varies from person to person and lack reliable indicator. This review summarizes clinical and animal studies on inflammation in neural circuits related to anxiety and depression and the evidence that neuromodulation therapies regulate neuroinflammation in the treatment of neurological diseases. Neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), electroconvulsive therapy (ECT), photobiomodulation (PBM), transcranial ultrasound stimulation (TUS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS), all have been reported to attenuate neuroinflammation and reduce the release of pro-inflammatory factors, which may be one of the reasons for mood improvement. This review provides a better understanding of the effective mechanism of neuromodulation therapies and indicates that inflammatory biomarkers may serve as a reference for the assessment of pathological conditions and treatment options in anxiety and depression.

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Introduction.

The prevalence of anxiety and depression continues to increase. Anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, and specific phobias, affecting 374 million people worldwide (4802 cases per 100,000 people) [ 1 ]. Depression, characterized by low mood, slowed thinking, and reduced volitional activity, affects 221 million people worldwide (3,152.9 cases per 100,000 people) in 2020 [ 1 ]. The Lancet estimated that the coronavirus disease 2019 (COVID-19) pandemic has resulted in an additional 53.2 million cases of major depressive disorder, which led to an increase in total disability-adjusted life years (DALYs) to 49.4 million, and 76.2 million cases of anxiety disorders, with total DALYs to 44.5 million worldwide in 2020 [ 1 ]. Symptoms of anxiety and depression often coexist, and comorbidity is associated with more severe symptoms, worse quality of life, greater recurrence, and higher suicide risk than either disorder alone. Despite the increasing incidence rates and heavy burden, the treatment effect for anxiety and depression is unsatisfactory. Conventional first-line treatment, including psychotherapy and medication, only achieves a 50% remission rate [ 2 ].

Neuromodulation techniques, including TMS, TES, ECT, DBS, and VNS, as well as the promising transcranial PBM and TUS, provide important adjunctive therapies for the treatment of anxiety and depression disorders [ 3 , 4 ]. The therapeutic power of neuromodulation comes from its ability to modulate the neural activity of specific brain regions and the related network function [ 5 ]. However, because of an insufficient understanding of the etiopathogenesis and pathophysiology of psychiatric disorders, even for a given symptom, the effective targets may vary from patient to patient. In addition, treatment results are generally determined by the patient’s report of symptoms, which may be lagging and unreliable. Thus, it is critical to identify objective markers to guide the formulation of treatment plans and evaluate their effectiveness.

Numerous studies have confirmed the association between chronic inflammation and depression, anxiety, and other psychiatric disorders, particularly those refractory to conventional medications [ 6 , 7 , 8 ]. Elevated levels of peripheral inflammatory biomarkers are present in patients with depression, and the level of inflammation correlates with the severity of specific symptoms [ 9 ]. Studies using positron emission computed tomography (PET) imaging with the 18 kDa translocator protein (TSPO) as a biomarker of microglia have shown that neuroinflammation exists in multiple brain regions in depression patients [ 10 , 11 , 12 , 13 , 14 , 15 ] (Fig. 1 ). Studies using animal models have also revealed pro-inflammatory factor release and microglial activation in the brains of animals, showing signs of anxiety and depression [ 16 , 17 , 18 , 19 ]. Interventions using drug therapy and neuromodulation for psychiatric disorders have been shown to reduce inflammation while relieving symptoms [ 18 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. We hypothesized that changes in inflammatory indices could be effective indicators for neuromodulation therapy. This review examines inflammatory alterations in the brain regions involved in anxiety-related threat and fear circuits and depression-related reward circuits. Furthermore, the modulation of inflammation in these key brain areas by various neuromodulation therapies was explored, with the aim of providing a reference for basic and applied research on neuromodulation therapy for the treatment of psychiatric disorders such as anxiety and depression.

Altered inflammation in the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), amygdala, hippocampus, insula, and other brain areas has been reported in vivo PET imaging studies in humans. The lateral habenula (LHb) and the dorsal raphe nuclei (DRN), which play an important role in depression, are found to have inflammatory changes in animal studies.

Key neural circuits and the brain regions involved in anxiety and depression disorders

Decades of studies have identified the brain areas involved in the pathophysiology of anxiety and depression. Owing to the development of optogenetic and chemogenetic techniques, neural circuits can be studied at higher spatial rates through finer control of neuronal activity, and the functional complexity of brain regions and nuclei has been discovered in animals. For example, BLA projections to the PFC, hippocampus, and lateral central amygdala (CeL) have a pro-anxiety effect, while projections to the bed nucleus of the terminal striatum and medial central amygdala (CeM) have an anti-anxiety effect. Activation of the medial prefrontal cortex (mPFC)-dorsal raphe nucleus (DRN) has an antidepressant effect, while activation of the mPFC-lateral habenula (LHb) has a pro-depressant effect [ 28 ]. The subcortical projection subgroup of the DRN (represented by the projection to the CeA) promotes anxiety, and the cortical projection subgroup (represented by the projection to the prefrontal cortex) is related to reward function [ 29 ]. In parallel, studies in humans revealed the role of large-scale functional brain networks in depression and anxiety. For example, major depressive disorder (MDD) was characterized by hyperconnectivity between default network seeds and regions of the hippocampus extending to the middle temporal gyrus, and areas of mPFC. These areas are believed to support internal mentation, e.g., self-referential thinking and affective decision-making [ 30 , 31 ].

Inflammatory changes in the specific brain regions of threat and fear circuits

Classically, the neural circuits closely associated with anxiety disorders are the threat-fear circuit [ 32 ], which includes the dorsolateral prefrontal cortex (DLPFC, not present in rodents), medial prefrontal cortex (mPFC, which corresponds to the medial precentral area, anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL) in rodents, with IL appearing to correspond to the subgenual cortex area, for example, [Brodmann area 25]) [ 33 ], amygdala (including the basolateral amygdala (BLA), lateral amygdala (LA), central amygdala (CeA), terminal bed nucleus), hippocampus, anterior insula, and other brain regions and nuclei. In general, external stimuli are transmitted to the amygdala and terminal bed nucleus through the thalamus and cortex. As the center of fear, the amygdala changes behaviors (freezing and startle), activate the autonomic nervous system, and transmit information to the hippocampus and bed nucleus of the terminal striatum [ 34 ]. PFC uses information gathered from various cortical and subcortical processing streams to predict the likelihood of threats in the environment, however, a persistent bias towards threat prediction can lead to a state of over-engagement in the defense system and anxiety [ 35 ]. Therefore, connections between these subcortical regions and the PFC play an important role in regulating anxiety. Altered inflammation in the amygdala, medial prefrontal cortex, dorsal cingulate, hippocampus, insula, and other brain areas has been reported in animal models and clinical studies.

The amygdala is a key brain region in emotion regulation and the generation of fear and anxiety. In recent years, studies have shown that social pressure and stress can cause inflammation, leading to changes in the human amygdala and related neural circuits, while changes in the amygdala activity can worsen inflammation, forming positive feedback. As early as 1982, Henke et al. found that stimulation of the CeA and anterior cingulate had a pro-inflammatory effect on gastric ulcers and that damage to these sites prevented stress from exacerbating gastric inflammation. This suggests that amygdala activity may have a pro-inflammatory effect and is not manifested only in the brain [ 36 ]. Conversely, inflammation increases amygdala activity [ 37 ], and individuals with higher levels of inflammation have a more active amygdala in response to social threats [ 38 ]. Acute social stress from an interview showed that increased amygdala activity and its strong coupling with the DLPFC were associated with higher levels of inflammation (higher interleukin or IL-6 and tumor necrosis factor or TNF-α) [ 39 ]. Zheng et al. found that microglial activation and pro-inflammatory cytokine production in the lateral amygdala and increased presynaptic glutamate release in a mouse model of lipopolysaccharide-induced neuroinflammation resulted in excitatory/inhibitory (E/I) imbalance, and that mice exhibited anxiety and depression-like behavior [ 40 ]. The anti-inflammatory factor IL-10 reverses abnormal gamma-aminobutyric acid (GABA) transmission in the amygdala, anxiety-like behavior, and substance dependence [ 41 ]. In adult male Sprague-Dawley rats, repeated social defeat leads to increased activation of microglia in the BLA and increased BLA discharge, whereas blocking microglial activation prevents anxiety-like behavior [ 16 ]. This indicates that there may be a mutually reinforcing effect between amygdala activity and inflammation levels, ultimately leading to anxiety.

Medial prefrontal and dorsal anterior cingulate cortices

Regions of the mPFC, including the rostral ACC, sgACC (Brodmann area 25), and medial frontal gyrus, have extensive relationships between the amygdala and others and are thought to be involved in emotion regulation. The dACC, often activated in patients with anxiety disorders, plays an important role in error detection, conflict monitoring [ 42 ], dealing with socially distressing emotions, and top-down activation of the autonomic nervous system [ 43 ].

Numerous neuroimaging studies have shown that elevated pro-inflammatory factors alter the activation of the mPFC and dACC. Women experiencing bereavement have increased IL-1β and TNF receptor II levels in their blood and show activation of the ventral mPFC (including the sgACC and orbitofrontal cortex) [ 44 ]. Healthy subjects have increased blood IL-6 levels, activation of the sgACC and dACC, and decreased functional connectivity between the sgACC, amygdala, and mPFC, as well as depressed mood after typhoid vaccination [ 45 , 46 ]. Increased activation of the dACC is found in subjects with increased neuroticism and obsessive-compulsive disorder, both of which are associated with increased anxiety and arousal, as well as increased inflammatory markers [ 47 ]. A neuroimaging study in patients with hepatitis C showed that treatment with interferon-alpha led to increased dACC activity [ 48 ]. Cytokine stimulation (Interferon or IFN-α) for 12 weeks in patients who are HCV-positive resulted in an increase in dACC activity in response to visuospatial attention error monitoring [ 48 ]. The above results suggest that neural activity in the mPFC and dACC is closely related to inflammation. In animal studies, the activation of the microglia and the elevation of the pro-inflammatory factors IL-1α and TNF-α were evident in the mPFC of mice with anxiety induced by repeated social deficits. Chronic stress has long been found to cause alterations in the neuronal function of the mPFC in humans and animals and Hinwood et al. found that such alterations may be related to the activation of the mPFC microglia [ 49 ]. Administration of complete Freud’s adjuvant (CFA) to mice-induced pain and anxiety-like behavior, significantly increased the expression of p-P38 and p-JNK in the ACC (this signaling pathway functions as a cytokine-inducing activator), activated the microglia and astrocytes, and increased the levels of pro-inflammatory factors IL-1β, TNF-α, and IL-6 [ 50 ].

Hippocampus

The hippocampus is located between the thalamus and medial temporal lobe of the brain and is part of the limbic system, involved in the regulation of cognitive functions, and has extensive neural network connections with emotion-related brain areas (the prefrontal cortex and amygdala). Several magnetic resonance imaging (MRI) studies have shown that amygdala and hippocampus volumes are significantly smaller in patients with post-traumatic stress disorder (PTSD) and social phobia than in healthy controls [ 51 , 52 ]. Numerous animal studies have shown that chronic stress leads to elevated levels of pro-inflammatory factors in the hippocampus and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammatory vesicles, a component of the innate immune system that acts as a pattern recognition receptor (PRR) and recognizes pathogen-associated molecular patterns (PAMP). The NLRP3 forms a caspase-1 activation complex, namely, NLRP3 inflammasomes, with adapter ASC protein PYCARD to shear the precursor of cytokine IL-1β and release active IL-1β [ 53 ]. TNF-α induced by the hippocampal microglia is significantly elevated in mice exposed to acute stress [ 54 ], and cytokines (IL-1β, TNF-α) released by the microglia can inhibit neurogenesis in the dentate gyrus [ 55 ], thereby promoting neuronal apoptosis [ 56 ] and increasing anxiety-related behavior [ 57 ]. In a meta-analysis encompassing multiple animal models of stress, all studies showed increased expression of the microglial cell surface marker ionized calcium-binding adapter molecule 1 (Iba1) in the hippocampus, and 75% of the studies showed increased Iba1 in the prefrontal cortex [ 58 ]. The hippocampal dentate gyrus of highly trait-anxious mice exhibited enhanced Iba1+ density and CD68+/Iba1+ microglial density. Oral administration of the microglial inhibitor, minocycline, reduced these changes and alleviated hyper anxiety in mice [ 23 ]. In a mouse model of PTSD constructed by footshock and situational reminder, the number of microglia in the hippocampus, prefrontal cortex, and amygdala was significantly increased and activated [ 59 ]. Twelve weeks of chronic mild stress-induced anxiety-like behavior in rats, and hippocampal microglial activation was detected in vivo by (18F) DPA-714 PET and in vitro by immunofluorescence staining and protein blotting [ 18 ].

In a meta-analysis of functional magnetic resonance imaging (fMRI) and PET in patients with PTSD, social anxiety disorder, atopic phobia, and in healthy individuals in fearful situations, patients showed stronger activity in the amygdala and insula than the controls did [ 60 ]. In healthy subjects injected with endotoxin, increased levels of glucose metabolism in the insula and decreased levels of metabolism in the ACC were observed using PET [ 61 ], decreased resting-state functional connectivity between the amygdala, anterior insula, and cingulate cortex was observed using fMRI [ 62 ]. In addition, endotoxin selectively enhanced amygdala activity while subjects were assessing socially threatening images [ 63 ], interestingly, female subjects (but not males) had increased activity in the dACC and anterior insula with increased IL-6 in response to social exclusion [ 64 ].

The above studies have shown that inflammation can affect the activity of anxiety-related brain regions such as the amygdala, ACC, insula, and functional connections within the circuit, thus causing emotional problems such as anxiety and reducing social adaptation.

Inflammatory changes in the specific brain regions of associated reward circuit in depression

The neural circuits closely associated with depression are the reward circuit and aversion center, mainly include the ACC, ventral tegmental area (VTA), ventral striatum comprising the nucleus accumbens (NAc) and ventral pallidum (VP), raphe nucleus, orbital prefrontal cortex (OFC) [ 65 ]. The LHb is the aversive center which produces negative emotions when active. Recent studies have found that ketamine targeting LHb has rapid and effective antidepressant effects [ 66 ]. In recent years, studies have strongly confirmed the presence of neuroinflammation as manifested by microglial activation in human emotional disorders, and this change varies with the course of the disease and treatment [ 10 , 11 ]. In a subsequent study, the authors confirmed that the duration of untreated major depression was a strong predictor of TSPO distribution volume (VT), that microglial activation was higher in depressive patients who had not been treated with medication for a longer time than in those with a shorter course of the disease, and that the degree of microglial activation no longer increased yearly when antidepressants were administered [ 13 , 14 ].

Prefrontal cortex and anterior cingulate cortex

In autopsies of suicidal patients with depression, the total microglia density was found to be no different from controls in the dACC. However, the proportion of primed over the ramified microglia was elevated, and the primed microglia expressed MHC class II antigen and CD68, leading to persistent neuroinflammation affecting neuronal function and causing psychiatric disorders. The presence of large numbers of macrophages in the perivascular area and the increased expression of Iba1 and monocyte chemoattractant protein-1 (MCP-1) suggest that the peripheral mononuclear cells were recruited by microglia and converted into macrophages in this brain region to participate in neuroinflammation [ 67 , 68 ]. Setiawan et al. performed PET with [18F] FEPPA in 20 patients with major depression and 20 healthy controls. The results showed that TSPO VT was significantly higher in the prefrontal cortex, ACC, and insula suggesting microglial activation, with TSPO VT in the ACC correlating with the severity of depression [ 15 ]. After typhoid vaccination in healthy individuals, the activity of the sgACC (associated with the etiology of depression) was enhanced in response to a task that implied an emotional face. In addition, inflammation reduces the connectivity of the brain regions involved in emotional processing, such as the sgACC to the amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus [ 45 ].

Animal models have demonstrated that chronic unpredictable mild stress(CUMS) promotes the production of pro-inflammatory cytokines in the mPFC. In the prefrontal area of stress-susceptible mice, the expression of TNF-α, cyclooxygenase (COX)-1, and Iba-1positive microglia cells increased [ 69 ]. Pan et al. found that a 12-week CUMS procedure remarkably increased PFC IL-1β mRNA and protein levels in depressive-like behavior of rats, and induced the activation of NLRP3 inflammasome. Moreover, the increased co-location of NLRP3 and Iba1 protein expression supported that microglia was the primary contributor to CUMS-induced neuroinflammation [ 70 ].

Ventral striatum

The ventral striatum, part of the striatum, is connected to the limbic system and receives nerve fiber projections from the prefrontal cortex (including OFC, vmPFC, and dACC), hippocampus, amygdala, and dopamine neurons in the VTA of the midbrain. It is involved in reward and emotional responses and is thought to be central to the brain’s reward system.

High levels of inflammation in patients with depression have been shown to affect cortical striatal reward circuits. In a resting-state fMRI of unmedicated patients with major depression, increased C-reactive protein (CRP) was associated with reduced connectivity between the ventral striatum and vmPFC and that of the dorsal striatum with the vmPFC and supplementary motor area (SMA), which are associated with depression’s core symptoms of bradykinesia and psychomotor slowing, respectively [ 71 ]. Yin et al. collected fMRI data from depressive patients with different levels of inflammation and found that increased plasma CRP was associated with reduced connectivity in widely distributed networks in the ventral striatum, ventral medial prefrontal lobe, and amygdala and that feeding these multivariate network features into machine learning algorithms could predict depressive symptoms with high accuracy [ 72 ]. In addition, artificially high levels of inflammation not only cause depressive mood but also alter ventral striatal activity and behavior responses to rewards and punishments [ 73 , 74 ]. Compared with placebo, healthy subjects injected with low doses of endotoxin experienced more pronounced depression and significantly reduced neural activity in the ventral striatum when participating in a task that was expected to receive a monetary reward [ 75 ]. When healthy volunteers who were vaccinated against typhoid faced the task of choosing a high-probability reward (win £1) and avoiding a high-probability punishment (loss £1), inflammation caused the ventral striatum and insula to mispredict reward and punishment, making the potential reward less attractive and the punishment more distasteful [ 73 ]. In healthy women, after experiencing the Maastricht Acute Stress Test and Montreal Imaging Stress Task, when completing a reward-punishment probability task paradigm, the ventral striatal reward prediction error signal transmission was decreased and correlated with an increase in IL-6 [ 74 ].

Dorsal raphe nucleus

The dorsal raphe nuclei (DRN) is located in a narrow area near the median suture of the brainstem, which is the largest septum nucleus and predominant 5-hydroxytryptamine neuron nucleus in the central nervous system. It is thought to be closely associated with psychiatric disorders such as anhedonia, anxiety, and depression. After stimulation by inflammatory factors, such as IL-1β, LPS, TNF-α, and Aβ42, microglia in the DRN are activated, IDO expression in the neurons is increased, the expression of tryptophan-5-hydroxylase (TPH, the rate-limiting enzyme in 5-hydroxytryptamine synthesis) is decreased, and the nucleus swells and degenerates [ 76 ]. Patients with inflammatory bowel diseases are often associated with psychiatric disorders such as depression or anxiety. Dextran sulfate sodium (DSS)-induced colitis rats exhibited depressive-like behavior and increased expression of the immediate-early gene FosB/ΔFosB, inducible nitric oxide synthase (iNOS), and reactive microglia in the DRN during the resolution phase of experimental colitis. Persistent central inflammation, particularly that of the DRN, may play an important role in the progression of depression and anxiety [ 77 ].

Lateral habenula

The habenula is located in the posterior part of the thalamus near the midline and can be divided into two regions: the medial habenula (MHb) and LHb. The LHb receives afferent information mainly from the basal ganglia and limbic forebrain and projects mainly to the rostromedial tegmental nucleus (RMTg) and midbrain monoaminergic nuclei. In various animal models of depression, the LHb is the only brain region that shows consistently increased activity, and a large body of evidence from animal models and human studies suggests a relationship between the LHb and various psychiatric disorders, particularly major depression [ 78 ].

Chronic unpredictable stress (CUS) increases the nuclear factor-κB (NF-kB) signaling pathway expression in the LHb, and injection of TNF-α into the LHb leads to depressive-like behavior in rats, which is conversely reduced by anti-inflammatory aspirin or NF-kB inhibitors [ 79 ]. Destruction of the LHb reduces inflammatory responses in the hippocampus and ameliorates hippocampal degeneration by reducing the expression of the PI3K/mTOR signaling pathway and apoptosis-related proteins, including phosphorylated p53, Bax, Bcl-2, and cleaved-caspase3, demonstrating the role of inflammatory responses of the LHb in depression [ 79 ]. Chronic social defeat stress (CSDS) causes depression in rodents, and RNA-seq analysis shows that this is associated with promoting the production of proprotein convertase subtilisin/kexin type 5 (Pcsk5) in LHb neurons, which activates the matrix metalloproteinase (MMP) 14-MMP2 pathway and promotes remodeling of the extracellular matrix to produce neuroinflammation [ 80 ].

Neuromodulation therapy reduces cytokines production and improves microglial function

Physical neuromodulation is a new therapeutic technique that has developed rapidly in recent years and includes non-invasive TMS, TES, ECT, PBM, and TUS, as well as invasive DBS and VNS. A growing body of studies has confirmed that these neuromodulation techniques can modulate inflammation while reducing psychiatric symptoms (Table 1 ).

Transcranial magnetic stimulation

TMS uses magnetic fields to interfere with neural activity in local superficial areas of the brain and has been approved by the US Food and Drug Administration (FDA) for the treatment of depression, addiction, and other disorders. The direct effect of TMS is to cause changes in the membrane potential of neurons at the target site and indirectly to cause other outcomes such as neurotransmitter release, improved synaptic plasticity, increased cell survival, and altered inflammatory and immune processes [ 81 ]. Low-frequency repetitive transcranial magnetic stimulation (rTMS) of cultured astrocytes reduced the expression of calcium signals and genes related to inflammatory damage pathways [ 82 ]. High-frequency (10 and 20 Hz) rTMS not only decreased the level of TNF-α but also increased the level of the anti-inflammatory factor IL-10 and significantly inhibited the classical activation and A1 marker expression of astrocytes [ 83 , 84 ]. And intermittent theta-burst stimulation of rTMS can regulate microglial polarization via TLR4/NFκB/NLRP3 signaling pathway [ 85 ]. In the rat of CUMS model, rTMS treatment significantly improved anxiety and depression-like behavior and reduced the levels of inflammatory factors TNF-α, iNOS, IL-1β, and IL-6 in the hippocampus [ 24 ]. In human studies, TMS modulates the levels of inflammatory factors during disease treatment. The most common target of TMS for depression is the left DLPFC [ 81 ], and the most commonly used for anxiety-related disorders is the right DLPFC [ 86 ]. rTMS at 10 Hz to the left DLPFC can reduce the serum levels of IL-1β and TNF-α in elderly patients with refractory depression, and this change correlates with Hamilton Depression Rating Scale (HDRS) scores [ 87 ]. Another study measured inflammatory cytokines in MDD patients who received bilateral theta-burst stimulation on DLPFC and found a slight decrease in IL-6 and CRP compared with the sham group, but not a statistically significant difference [ 88 ]. These findings suggested rTMS as a non-pharmacological approach, can target anti-inflammation, and regulate microglial function in depression and anxiety disorders.

Transcranial electrical stimulation

TES, including constant (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS), modifies brain function by applying weak electrical currents to the scalp. Since its introduction in the 1980s, this method has been used to improve a variety of diseases, such as mood [ 89 ], cognitive [ 90 ], and motor disorders [ 91 ]. It is generally accepted that TES can alter cortical excitability, for example, anodal stimulation has an excitatory effect, cathodal stimulation has an inhibitory effect, and alternating current can modulate endogenous brain oscillations [ 92 , 93 ]. Accumulating evidence suggested that non-invasive TES could affect inflammatory response and microglial function. tDCS treatment inhibits the expression of IL-1β, IL-6, and TNF-α in rats, thereby reducing the hippocampal inflammatory response [ 94 ]. Pikhovych et al. suggested anodal tDCS to reduce Iba1-positive microglia in the cortex of healthy mouse [ 95 ]. Another experiment found that cathodal tDCS increased the number of iNOS-positive M1-polarized microglia without affecting CD 206-positive M2-polarized microglia [ 96 ]. Meanwhile, Brunoni et al. measured plasma levels of various cytokines, including IL-1β, IL-6, IL-10, and TNF-α, before and after tDCS treatment (anodal stimulation on left DLPFC and cathodal stimulation on the right DLPFC) in depressed patients, showing all of these factors decreased after tDCS treatment, but this decrease was not significantly different from the sham group [ 97 , 98 ]. And using tDCS for patients with depression with type I or II bipolar disorder, not only was the patient’s higher baseline IL-6 concentration associated with therapeutic efficacy, but the patient’s plasma IL-8 concentration also decreased significantly after treatment [ 21 ]. In recent years, there has been some exploration of using tACS to treat mood disorders. Wang et al. used 77.5 Hz tACS on the forehead to treat depression and achieved positive results [ 99 ] A case series reported 40 Hz tACS leading to a significant decrease of microglia activation as measured by [11 C]-PBR28 [ 100 ]. Thus the anti-inflammatoy mechanisms of tDCS and tACS make them a particularly promising avenue in treating various emotional conditions.

Electroconvulsive therapy

ECT is the longest-standing and most widely used neuromodulation therapy for the treatment of refractory depression, particularly for patients with suicidal tendencies or depressive symptoms. Electrodes are generally placed bilaterally in the temporal or frontal regions, and electrical stimulation is used to induce generalized seizures, thereby improving depressive symptoms. Animal studies reported a general activation of inflammatory molecules and pathways within 4 h of receiving ECT [ 101 ]. An hour after three or four ECT courses, the protein and mRNA expression of NF-κB was increased and the transcription of the COX2 gene, involved in an acute inflammatory response, was increased in rats [ 102 , 103 ]. ECT also reduces microglial activation [ 104 ] and cytotoxicity by inhibiting T cell stimulatory and chemokine expression and iNOS expression, nitric oxide, and reactive oxygen species (ROS) production [ 105 ]. In human studies, the efficacy of ECT for depression are related to enhanced cortical neuroplasticity [ 106 ] and improved connectivity of the limbic system and prefrontal network [ 107 ]. And in terms of peripheral and central inflammation, some studies have suggested that ECT in patients with depression activates peripheral blood mononuclear cells in 30 min [ 108 ], increases circulating pro-inflammatory factors such as IL-1β and IL-6 at 3 h, and falls back to baseline at 24 h [ 109 ]. Conversely, other studies have suggested that ECT has anti-inflammatory effects, and researchers performing ECT in patients with depression found reduced plasma levels of pro-inflammatory factors IL-6 and TNF-α and increased hippocampal volume [ 110 ]. In addition, ECT significantly reduced plasma quinolinic acid and improved the unbalanced kynurenine pathway affecting the monoaminergic neurotransmitters in patients with major depression [ 111 ]. These findings supported the efficacy of ECT in the treatment of refractory depression potentially through a neuroinflammatory mechanism.

Photobiomodulation

PBM is a relatively safe and well-tolerated neuromodulation technique that uses artificial light to irradiate specific brain areas. Its effectiveness in treating depression has been reported in clinical and animal models [ 112 ]. Some studies suggest a relationship between increased mitochondrial energy metabolism and local cerebral blood flow as an action mechanism of PBM [ 113 ]. In addition, light therapy may have anti-oxidative stress and anti-inflammatory effects by modulating ROS, whose brief burst can activate the redox-sensitive transcription factor, NF-kB, nitric oxide, cyclic AMP, calcium, etc. In cell experiments, PBM can reduce inflammatory markers, such as COX-2, prostaglandin E2etc, and regulate the expression and secretion of activated normal T cells [ 114 ]. Hwang et al. found that 405, 532, and 650 nm light reduced IL-8 expression, and 405 nm light also reduced IL-6 expression [ 115 ]. Huang et al. found that the antidepressant effect of PBM involved activation of the retina-ventrolateral genicular nucleus of the thalamus/interlobar-lateral habenula pathway to regulate depressive mood [ 116 ]. Laser treatment (660 nm, 100 mW) at 5 irradiation points on the head increases the level of IL-1α in the hippocampus of aged rats and decreases the levels of IL-5 and IL-8, thus improving the inflammatory response [ 117 ]. The abdomen of pregnant rats exposed to 808 nm near-infrared light was related to the effect of light on promoting the transformation of pro-inflammatory microglia to the anti-inflammatory M2 type [ 118 ]. Clinically, transcranial PBM therapy using near-infrared light in 10-Hz pulsed mode appears to be a hopeful technique for the treatment of MDD [ 119 ], suggesting that the effects of PBM on modulating neurological function in the brain for the treatment of depression may be related to the modulation of microglial activity and central inflammatory responses.

Transcranial ultrasound stimulation

Low-intensity focused ultrasound stimulation (LIFUS) is a very promising new non-invasive neuromodulation technology. LIFUS activates or inhibits neural activity by transmitting acoustic mechanical vibrations to stimulate specific areas of the brain and has the unique advantage of high spatial specificity and targeting of deep brain nuclei compared to other neuromodulation techniques [ 120 ]. Nonthermal mechanical mechanisms such as through mechanosensitive ion channels and voltage-gated ion channels mediating altered neuronal firing [ 121 ] is the action of LIFUS for neuromodulation. Animal and cell experiments have demonstrated that LIFUS changed the expression of the inflammatory signaling pathway to play an anti-inflammatory role. LIFUS treatment was found to inhibit LPS-induced activation of TLR4/NF-κB inflammatory signals and reduced the protein levels of TNF-α, IL-1β, and IL-6 in LPS-treated mice [ 122 ]. Furthermore, LIFUS significantly decreased the Bax/Bcl-2 ratio in the microglia following LPS treatment [ 123 ]. LIFUS can normalize the expression of not only inflammatory cytokines (NF-κB, TNF-α, IL-1β) but also downstream signaling proteins such as COX-2 and NF-κB [ 124 ]. In animal studies, LIPUS stimulation of the vmPFC or left PFC improved the rat’s anxiety-depression-like behavior [ 125 , 126 ]. In human studies, Sanguinetti et al. found that TUS (2 MHz, 15 s) in the right inferior frontal gyrus increased positive mood for 15–30 min in healthy subjects [ 127 ]. Reznik et al. randomly divided 24 mild-moderate depressed college students into two groups, and the true stimulation group received 5 sessions of TUS (500 kHz, PRF 40 Hz, 30 s) at the right fronto-temporal area, and the results showed that TUS improved anxiety symptoms, but not depressive symptoms. In the future, LIFUS will have a great application prospect in the treatment of neuropsychiatric diseases by influencing the inflammatory response and accurately regulating the function of a neural circuit.

Deep brain stimulation

DBS refers to the stereotactic implantation of electrodes into specific brain regions, and the application of electrical impulses to stimulate neuronal activity for disease treatment. DBS for anxiety and depression is still in the clinical research phase and not yet mature. Some studies suggest that DBS treatment leads to neuroinflammation, including the activation of astrocytes and microglia, as confirmed in autopsies of patients treated with DBS [ 128 , 129 , 130 ] and in animal studies with implanted electrodes [ 131 , 132 , 133 ]. It has been suggested that acute inflammation caused by electrodes implantation can alleviate depression, for example, in subgenual cingulated gyrus (SCG) DBS, a non-pharmacological treatment for refractory MDD, where a “biphasic effect” has been observed clinically, whereby patients show significant improvement in the first week after electrode implantation, and thereafter the efficacy declines until six months after the procedure when a plateau is reached with slow improvement [ 134 ]. The immediate postoperative ameliorative effect is associated with acute inflammation caused by electrodes, accompanied by increased expression of glial fibrillary-acidic-protein, inflammatory mediators (e.g., TNF-α), and p11; the latter plays an important role in the production and utilization of 5-HT [ 135 ].

However, an increasing number of studies have suggested that DBS can alleviate chronic inflammation and that the anti-inflammatory effect may be a mechanism for its efficacy. DBS of the lateral cerebellar nucleus in rats inhibited pro-inflammatory gene expression and microglial activation in the surgical group, suggesting that the efficacy of DBS may be related to its anti-inflammatory effects [ 136 ]. Stimulation of the anterior thalamic nucleus with DBS for one week resulted in significant decreases in caspase3 activity and interleukin-6 (IL-6) levels in the hippocampus of rats, showing anti-inflammatory and anti-apoptotic effects. However, DBS did not affect TNF-α levels, suggesting that the effect of DBS on cytokines may be specific [ 137 ]. The anti-inflammatory effects of DBS may be related to CX3CL1/CX3CR1 signaling. DBS in the subthalamic nucleus reduced the expression of fractalkine (CX3CL1) and its receptor (CX3CR1), inhibited microglial activation and NF-κB expression, reduced pro-inflammatory cytokines IL-1β and IL-6, and increased the expression of the extracellular signal-regulated kinase (ERK) and cleaved-caspase3 [ 138 ], suggesting the anti-inflammatory effect caused by DBS treatment.

Vagus nerve stimulation

VNS is a stimulating electrode placed on the vagus nerve (most often in the neck) that delivers low-frequency, intermittent electrical pulses, approved for refractory depression in 2005 by the FDA. Afferent vagus nerve fibers terminate in the medulla, from which there are projections to many areas of the brain, including the limbic forebrain. VNS affects many brain regions involved in depressive pathology, neurotransmitters (serotonin, norepinephrine), and signal transduction mechanisms (brain-derived neurotrophic factor—tropomyosin receptor kinase B), but the exact mechanism of action is unclear. VNS attenuates the inflammatory response, peripherally (cytokine alterations) and centrally (reduced microglial activation), which is known as the parasympathetic anti-inflammatory pathway [ 139 , 140 ]. Stress induces sympathetic excitation, increased catecholamine release, and activation of the NF-kB pathway [ 141 ] associated with increased brain and peripheral cytokine expression [ 142 ]. α- and β-adrenergic receptor activators indirectly activate NF-kB [ 143 ], and α-adrenergic receptor blockers reduce stress-induced IL-6 elevation in peripheral blood in humans [ 144 ]. Parasympathetic excitation and acetylcholine release activate the A7 subunit of the nicotinic acetylcholine receptor (NAChR), which regulates the transcription and translation of cytokines and exerts anti-inflammatory effects [ 145 , 146 , 147 ]. Studies have shown a 42–53.1% two-year remission rate for refractory depression with VNS (≥50% reduction in HDRS scores from baseline) [ 148 , 149 ]. And a growing number of studies have found that non-invasive VNS (percutaneous or transaural) is as effective as invasive direct stimulation in treating refractory epilepsy [ 150 ], Alzheimer’s disease [ 151 ], pain, anxiety, depression, etc. [ 152 ], predicting the promising application in the treatment on neuropsychiatric disorders.

Neuromodulation therapies that target and disrupt a dysfunctional brain focus, region, or network offer important adjuvant therapies for refractory psychiatric disorders. Advances in our understanding of neuroanatomical networks and the mechanism of stimulation, coupled with developments in material science, miniaturization, energy storage, and delivery, will expand the use of neuromodulation devices in the future. Clinically accessible biomarkers that can indicate the physiological changes precede and after treatment are valuable.

As stated above, mental illness is closely related to the inflammatory response of the body, and inflammation is not only present in the periphery but also affects the central neural circuits that are usually targeted by neuromodulation therapy [ 153 , 154 ]. Almost all neuromodulation methods have been reported to affect the inflammatory response of the body during application. It is reasonable to speculate that the detection of clinically accessible TSPO-PET and peripheral inflammatory factors could be used as biomarkers.

The use of TSPO as a clinical neuroimaging biomarker of microglia activation and neuroinflammation has increased exponentially in the last decade. Elevated TSPO binding was observed in six of seven studies of unmedicated patients with MDD [ 155 ]. Attwells et al. found that elevated prefrontal and anterior cingulate TSPO signal in patients with refractory MDD predicted a reduction in depressive symptoms in patients taking celecoxib (a nonsteroidal anti-inflammatory drug), which indicate that TSPO-PET could predict treatment response [ 156 ]. These studies support the implication value of TSPO-PET. However, psychiatric disorders are more heterogeneous in neuropathology and several factors may affect the reproducibility of results and retard the broad use of TSPO-PET at present. These factors include TSPO radioligand used (R-PK11195 or second generation), short-term and long-term outcomes, PET imaging quantification with and without radioligand plasma input data, medicated vs naïve subjects, as well as corrections for the human TSPO polymorphism and vascular radioligand binding [ 157 ]. Thus, large sample size studies and standards of operation are needed so that future studies and applications can be appropriate. Fortunately, improved radioligands, especially [11C]ER176, overcome some of the major drawbacks of earlier tracers making the TSPO-PET technique more promising as a neuroinflammatory index.

Numerous studies have provided evidence of increased levels of inflammatory markers in depression and anxiety. Studies have shown that inflammatory factors IL-1β, IL-6, TNF-α, and CRP are elevated and anti-inflammatory factors IL-4, IL-8, and IL-10 are decreased in peripheral and cerebrospinal fluid and correlate with patients’ symptoms and disease duration in depression and anxiety [ 158 , 159 , 160 ]. Remission of depressive symptoms accompanied by a decrease in inflammatory factors [ 161 ]. Available data suggest that multiple kinds of antidepressants significantly downregulate a wide array of peripheral biomarkers such as IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-10, CRP, or IFN-γ and inhibit inflammation in the brain [ 162 ].

For the question of whether peripheral cytokines reflect the inflammatory conditions in CNS, there are channels for peripheral inflammatory factors to interact with central inflammation:(1) cross the blood-brain barrier through leakage zones, (2) active transport of supersaturated transport molecules, (3) activation of cerebrovascular endothelial cells and other cell types (including perivascular macrophages, which then produce cytokines and other inflammatory mediators in the brain), and (4) bind to cytokine receptors with peripheral afferent nerve fibers (e.g., vagus nerve) [ 163 ]. (5) propose inflammatory vesicle activation and immune cell transport [ 164 , 165 ]. Studies also showed a positive relation between peripheral inflammatory factors and central inflammation in depression. For example, in a sample that examined three cohorts (two of whom were experiencing MDD), peripheral inflammation factors (prostaglandin E2/CRP) and (TNFα/CRP) consistently correlated with brain TSPO signal and had sufficient positive predictive value to be considered for use in clinical trials [ 166 ]. Not all patients with mood disorders have elevated levels of inflammation, but in patients with a high inflammatory background, pro-inflammatory factors are suggestive of the condition and may benefit future trials exploring anti-inflammatory treatment options for anxiety and depression.

There are limitations that remain. The activation of neuroinflammation is not consistently reported by all patients and appears not to be specific to any particular category. We need to understand the underlying physiology of microglial activation. In addition, neuromodulation has shown promising effects in reducing cytokines and improving microglial polarization; however, the exact mechanism is unclear and needs to be further explored. Furthermore, some studies have shown that neuromodulation techniques play a role in astrocyte-associated inflammatory responses, which may lead to confusion. Notably, the neuromodulation technique did not show these effects in healthy individuals, suggesting that it may reduce an abnormal excess of inflammatory and pro-inflammatory factors and increase anti-inflammatory factors to promote the restoration of homeostasis when the inflammatory balance is disrupted [ 167 , 168 ]. The key challenges to effective treatment are defining the targets for stimulation and multiple configurable stimulation measures, including stimulation pathways, frequency, pulse width, duration, intensity, and stimulation duration. The application of neuroinflammatory biomarkers in neuromodulation therapies will inevitably rely on more clinical evidence and data science to achieve the best outcomes, particularly chronically obtained data.

Inflammatory biomarkers may serve as a reference for the evaluation of anxiety and depression and treatment selection. Neuromodulation therapy targeting neural circuit dysfunction to treat affective disorders by reducing neuroinflammation provides a better understanding of the pathogenesis of the disease and objectively evaluates the efficacy of physical therapy.

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Acknowledgements

We acknowledge the support of the Natural Science Foundation of Beijing (No. 7212048), the National Natural Science Foundation of China (No. 82071483), and the National Key R&D Program(2021YFC2501403).

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Bingqi Guo, Mengyao Zhang, Wensi Hao, Yuping Wang, Tingting Zhang & Chunyan Liu

Beijing Key Laboratory of Neuromodulation, Beijing, 100053, China

Institute of sleep and consciousness disorders, Center of Epilepsy, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China

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This review was drafted by BG, revised and expanded upon by TZ and CL. MZ and WH helped proof the manuscript. YW reviewed the manuscript. All authors contributed to the article and approved the submitted version.

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Guo, B., Zhang, M., Hao, W. et al. Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression. Transl Psychiatry 13 , 5 (2023). https://doi.org/10.1038/s41398-022-02297-y

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The Role of Inflammation in Depression and Fatigue

Chieh-hsin lee.

1 Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada

Fabrizio Giuliani

2 Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Depression and fatigue are conditions responsible for heavy global societal burden, especially in patients already suffering from chronic diseases. These symptoms have been identified by those affected as some of the most disabling symptoms which affect the quality of life and productivity of the individual. While many factors play a role in the development of depression and fatigue, both have been associated with increased inflammatory activation of the immune system affecting both the periphery and the central nervous system (CNS). This is further supported by the well-described association between diseases that involve immune activation and these symptoms in autoimmune disorders, such as multiple sclerosis and immune system activation in response to infections, like sepsis. Treatments for depression also support this immunopsychiatric link. Antidepressants have been shown to decrease inflammation, while higher levels of baseline inflammation predict lower treatment efficacy for most treatments. Those patients with higher initial immune activation may on the other hand be more responsive to treatments targeting immune pathways, which have been found to be effective in treating depression and fatigue in some cases. These results show strong support for the hypothesis that depression and fatigue are associated with an increased activation of the immune system which may serve as a valid target for treatment. Further studies should focus on the pathways involved in these symptoms and the development of treatments that target those pathways will help us to better understand these conditions and devise more targeted treatments.

Introduction

Depression affects more than 168 million people worldwide and is one of the major causes of disease burden, accounting for the fifth highest global years lived with disability; this rate rises to the third highest in high income countries given the higher rate of prevalence ( 1 , 2 ). Depression is also one of the key factors for impaired quality of life in patients affected by chronic diseases ( 3 ). In diseases such as multiple sclerosis (MS), it has also been linked to increased suicidality, which accounts for up to 7.5 times higher portion of death in MS patients than in the age-matched general population ( 4 – 6 ). Fatigue, defined as “a subjective lack of either physical and/or mental energy that… [interferes] with usual and desired activities” ( 7 ), is strongly associated with mental health symptoms such as depression and anxiety ( 8 , 9 ). Fatigue often arises in chronic conditions and can have a prevalence as high as 99% as seen in cancer patients ( 10 ). Fatigue is one of the most debilitating symptoms of MS, with 69% of patients rating it as one of their worst symptoms and 60% reporting that it makes their other symptoms worse ( 11 ). Fatigue is also strongly linked to a worsening of one's quality of life ( 12 , 13 ).

The most recent literature has shown an undeniable relationship between the activity of the immune system and neurological changes, along with subsequent psychological symptoms ( 14 ). One of the main focuses of this field is the role of the immune system in mental health and psychological disorders. Immune-mediated diseases of the central nervous system (CNS), such as MS ( 15 ), and disease modifying therapies that affect the immune system such as interferons ( 16 ) are good models to explore this association. Studies have extensively probed these interactions and found that subjects with depression and fatigue have higher levels of inflammatory immune activation, along with a host of other immunological changes ( 17 , 18 ). These changes can, among other things, be used to predict treatment efficacy and future fluctuations in patient well-being.

While over the years there has been a significant amount of scientific literature on depression and fatigue ( 17 , 19 – 23 ), there is emerging new evidence on the role of depression and fatigue in immune-mediated disorders. Here, we will review the existing knowledge regarding the links between immune response, psychological well-being, and structural changes in the brain. We will then analyze the literature regarding the presence of depression and fatigue in immune-mediated disorders. We will look at the relationship that depression and fatigue have with their existing treatments including those that do not specifically target the immune system. We will conclude by discussing some of the difficulties encountered in this line of experimentation and provide direction for potential future research.

Immune Response and Depression and Fatigue

Early observations about the link between the immune system and psychological responses occurred in the context of cytokine-induced sickness behavior and immunotherapies such as interferon alpha (IFNα) in the context of hepatitis C treatment ( 24 , 25 ). Cytokine-induced sickness behavior is a syndrome characterized by decreased activity, depression, and loss of energy because of the increased circulating levels of proinflammatory cytokines. It has been explored as a model for the role that the immune system plays in behavioral changes in both animals and humans ( 19 , 26 ). The inflammatory immune response and cytokine levels have been associated with both depression and fatigue in a large body of literature across different disorders ( 10 , 27 – 32 ). Another early line of research involved IFNα therapies, which activate an inflammatory antiviral response and are used clinically as a treatment for hepatitis C ( 33 ). Renault et al. ( 24 ) found that 17% of patients treated with IFNα developed psychiatric side effects, but also noted that the symptoms improved with the cessation of treatment. However, a recent study found that patients who suffered from depression after IFNα treatment had a significantly higher risk of having recurrent depressive episodes, which suggests that these mood changes are not a transient phenomenon but more similar to normal recurrent depressive episodes ( 34 ). The same effect on mood has also been shown with similar treatments in other disorders, such as melanoma, and Capuron et al. ( 33 ) found that these changes responded to antidepressant treatment.

Previous meta-analyses have shown an increase in proinflammatory cytokines, such as TNFα and IL-6 ( 27 ), in people suffering from depression ( Figure 1 ). In a more recent, larger scale meta-analysis a greater range of changes have been described in people with depression, including higher levels of TNFα, IL-6, IL-13, IL-18, IL-12, IL-1RA, and sTNFR2, along with a decrease in the proinflammatory cytokine IFNγ ( 18 ). A wide variety of chemokine levels have also been demonstrated to be significantly affected, including increased CCL2 (MCP-1), CXCL4, and CXCL7, with CCL4 having significantly lower levels in serum ( 31 , 35 ). Studies found increased levels of serum IL-1RA, IL-6, TNFα, and IP-10 in cancer patients with fatigue ( 29 , 36 ). There is also evidence that these changes may be predictive of future depression. A longitudinal study showed that people with higher IL-6 at age nine are more likely to have depression at age 18 in a dose dependent manner, even adjusting for a variety of factors ( 37 ). Gimeno et al. ( 38 ) conducted a study in adults that showed similar results, with CRP and IL-6 levels at baseline predicting cognitive symptoms of depression 12 years later.

Links between peripheral inflammation and changes in the CNS in depression and fatigue. Increased inflammation is seen in the periphery in both depression and fatigue. This inflammation leads to increased permeability of the BBB, allowing for easier entry of inflammatory molecules or immune cells into the CNS. Inflammatory signaling in the CNS leads to both structural and functional changes, with the hippocampus being the location of many of the changes. BBB, Blood–brain barrier; CNS, Central nervous system; CRP, C-reactive protein; IFN, Interferon; IFNAR1, Interferon-alpha/beta receptor alpha chain; IL, Interleukin; IP-10, Interferon gamma-induced protein 10; TNF, Tumor necrosis factor; NK, Natural killer cell; T reg , Regulatory T cell; LTP, Long-term potentiation.

Other findings indicate higher levels of TNFα and IFNγ in in vitro -stimulated CD8+ T cells isolated from patients with depression and IFNγ levels correlate with the severity of the condition ( 39 , 40 ). In contrast, a suppression of immune responses has also been described in patients with depression ( 41 ). An early meta-analysis found that patients with depression have a higher leukocyte number and CD4+/CD8+ ratio, as well as lower natural killer (NK) cell count with impaired T and NK cell activity ( 17 ). There are a limited number of studies exploring the seemingly conflicting findings of immune activation and suppression in depression. More recent studies have shown that both can occur in the same patient, with NK and regulatory T cell (T Reg ) activity suppressed and inflammatory monocytes activated ( 42 , 43 ).

The depressive symptoms resulting from IFNα treatment, and especially the evidence suggesting that it has a long-term effect, is strong evidence for a causal link between inflammatory activation and depression. In addition, further evidence is provided by other studies showing that higher IL-6 levels predict future development of clinical depression. One of the potential mechanisms for these changes in the periphery is an increased activation of inflammatory monocytes and T cells and a higher CD4+/CD8+ ratio, which is coupled with supressed T Reg activity. This combination of higher inflammatory activation and less anti-inflammatory inhibition results in a more proinflammatory peripheral environment seen in patients with depression and fatigue.

Inflammation and Changes in the Brain

The role of inflammation in depression and fatigue has led researchers to examine the effects that peripheral inflammation has on the CNS. Some changes occur at the level of the blood brain barrier (BBB), which separates the CNS parenchyma from the peripheral blood circulation. TNFα cause changes in the endothelial cells constituting the BBB, resulting in reduced tight junction protein expression, larger extracellular gaps and increased permeability in animal models and in vitro , all of which are restored by treatment with anti-inflammatory drugs ( 44 , 45 ) ( Figure 1 ). An increase in proinflammatory cytokine levels including TNFα have occurred in patients who have suffered from a myocardial infarction and is associated with disruption of the BBB integrity in animal models and elevated rates of depression ( 46 ). CNS inflammation has also demonstrated that it disrupts the BBB in both MS and its animal model, experimental autoimmune encephalitis (EAE), allowing for easier entry of both cytokines and immune cells into the brain ( 47 , 48 ). This increased permeability of the BBB may be one of the reasons why patients with immune-mediated diseases like MS have worse psychological symptoms compared to those with other chronic disorders.

Inflammatory changes in the brain parenchyma have also been associated with depression. Increased levels of TNFα in the hippocampus and striatum have been associated with anxious and depressed behavior in EAE studies, with the changes in the striatum occurring before the onset of clinical symptoms ( 49 , 50 ). IL-1β has shown to decrease neurogenesis in vitro in human hippocampal progenitor cells, a common finding in depression, via activation of the kynurenine pathway; this effect being partially rescued by both inhibitors of this pathway and traditional antidepressants ( 51 , 52 ).

At a cellular level changes with TNFα inducing release of glutamate by activated microglia in vitro , leading to excitotoxic damage in the surrounding neurons have also been reported in the literature ( 53 ). Type I interferons act through the interferon receptor chain 1 pathway in mouse BBB epithelial cells to cause impairment of long-term potentiation in hippocampal neurons in vivo , leading to depressive-like behaviors ( 54 ). These changes suggest a potential mechanism for the immune system's role in inducing neurological and psychological symptoms even in the absence of an altered BBB integrity.

Studies also examined the effect on the brain structure of immunotherapies associated with depression ( Figure 1 ). IFNα treatment in patients with hepatitis C changed striatal microstructure, measured by MRI techniques such as quantitative magnetization transfer (qMT), as early as 4 h after injection, and these changes predicted development of fatigue 4 weeks later ( 30 ). Another study found that changes in brain global connectivity, which were correlated with mood changes, also occurred within 4 h from the injection of IFNα ( 55 ). Infusion of endotoxins, which also induce an inflammatory response, resulted in increased depressive mood and reduced ventral striatal response to reward cues. This indicates anhedonia, a key symptom of depression ( 56 ).

Overall, inflammation causes disruptions in the BBB along with cellular and structural changes within the CNS. In vitro and in vivo animal models have shown that inflammation decreases neurogenesis in the hippocampus, induces glutamate release from microglia, and impairs LTP. Human MRI studies have shown that IFNα and endotoxin treatments result in rapid changes in white matter structure, brain global connectivity, and functional activation, all of which are linked to depression and fatigue.

Immune Activation Is Associated With Depression and Fatigue

Higher rates of depression and fatigue have been shown across a broad range of conditions associated with activation of the immune system such as allergies, autoimmune diseases (Type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis), and infections (sepsis). Patients with both atopy and asthma have a roughly 50% increased rate of depression ( 57 , 58 ). Du et al. ( 59 ) found that 35.9% of asthmatic patients suffer from depression and that TNFα levels were significantly higher in the depressed cohort, with IFNγ being significantly lower.

In diabetes, activated inflammatory immune response is implicated in its pathogenesis, with immune activation being involved in the development of both type 1 and type 2 diabetes ( 60 ). Meta-analyses have found that the prevalence of depression in patients with diabetes is up to twice that of people without the disease ( 61 , 62 ). Associations have been shown between depression and serum levels of CRP, IL-1β, IL-1RA, and MCP-1 in type 2 diabetes patients, with all serum levels being significantly higher in those who are depressed ( 63 ).

A meta-analysis showed that 30% of patients with systemic lupus erythematosus (SLE) suffer from depression using the standard Hospital Anxiety and Depression Scale subscale for depression (HADS-D) ( 64 ). Studies have also demonstrated that higher levels of fatigue are associated with increased risk of depression and that there is no association with disease severity in patients with SLE ( 65 , 66 ). A review by Schmeding and Schneider ( 67 ) found that up to 92% of patients with SLE are fatigued, without correlation with disease severity. Significantly higher TNFα and lower IL-10 levels have been shown in depressed SLE patients and have been associated with worse depression scores ( 68 , 69 ).

Depression also has a high prevalence in patients with rheumatoid arthritis (RA). Studies showed a 74% increased risk of depression compared to controls with a prevalence as high as 73.2%, and a meta-analysis found that 16.8% of RA patients suffer from it ( 70 – 72 ). Up to 80% of patients who are diagnosed with RA experience clinically relevant fatigue ( 73 ). Kojima et al. ( 74 ) showed that there was a positive correlation between CRP levels and depression severity in RA patients. Serum CRP levels along with erythrocyte sedimentation rate (ESR), a marker for the severity of inflammation, also have a significant correlation with fatigue ( 75 ). A Cochrane review examined a variety of anti-TNF and other biologic agents used in RA and found that they had significant effects on the fatigue experienced by patients, further strengthening the suggestion that fatigue may in part related to immune responses ( 76 ).

Patients with MS have a lifetime prevalence of 25–50% for depression, with an incidence rate ratio of 2.41 compared to age- and sex-matched controls ( 77 – 79 ). An increase in the incidence and prevalence of depression, along with an increase in the rate of prescriptions for antidepressant, occur as early as 2 years before MS diagnosis ( 80 , 81 ). The prevalence of fatigue is even higher than that of depression, with a prevalence as high as 75% ( 82 – 85 ). In later phases of MS the prevalence of fatigue can increase up to 95% ( 86 ). However, there is a large variability in results regarding the role of immune activation in depression and fatigue in MS patients, with studies describing contradictory results. Some studies have demonstrated an increase in peripheral blood cell-derived TNFα mRNA along with circulating TNFα and IFNγ in MS patients with fatigue ( 87 , 88 ). Brenner et al. ( 89 ) also showed that higher CSF IL-6 levels are significantly associated with both increased depression and fatigue scores. Alternatively, a study by Malekzadeh et al. ( 90 ) found that TNFα and IFNγ, along with 10 other cytokines, did not vary significantly between fatigued and non-fatigued patients, although the study did find significant correlation with IL-6 levels. In contrast, Giovannoni et al. ( 91 ) showed that circulatory CRP and sICAM-1 levels are not correlated with fatigue.

The link between immune activity and depression and fatigue is not only shown in immune related disorders but also in cases where the immune system is activated in response to infections. Sepsis is a systemic immune response to an infective agent which leads to broad proinflammatory activation. Even after the resolution of the condition, survivors have a persistently higher concentration of circulating inflammatory markers and a range of long-term symptoms leading to decreased quality of life ( 92 – 94 ). Davydow et al. ( 95 ) found that while survivors of sepsis have a higher prevalence of depression compared to the general population, this was not significantly higher than that preceding the infection. This high prevalence of depression in patients pre-sepsis is consistent with other findings that demonstrate psychosocial stress increases depression and immune activation ( 96 ) and is associated with a greater short-term risk of sepsis ( 97 ). There have been very few studies on post-sepsis depression in humans, however, studies in animal models have shown sepsis-like conditions leading to affective changes ( 98 ). These studies in animal models have also found that immune suppression, by way of dexamethasone or by inhibiting the NF-κB pathway, reduces the resulting depressive-like behavior in the animals ( 98 , 99 ). There may be a potential role for the “priming” of the immune system by condition such as sepsis or treatments like IFNα, which show an increased risk of developing depression later on ( 34 ). Further studies are needed to establish whether previous immune activation primes the immune system to be more sensitive to stress or other insults, leading to an increased risk of depression and fatigue in the future.

Immunomodulatory Effects of Antidepressant and Anti-Fatigue Therapies

Changes in the levels of immune markers have also been associated with the response to antidepressant therapies and found helpful in predicting treatment efficacy ( Table 1 ). In mice treated with LPS, serotonin reuptake inhibitor (SSRI) and serotonin–norepinephrine reuptake inhibitor (SNRI) administration lead to decreased serum levels of TNFα and increased levels of IL-10 ( 104 ). In the repeated social stress model, treatment with tricyclic antidepressant (TCA) decreased microglial expression of IL-6 mRNA both in vivo and following ex vivo stimulation, where TNFα and IL-1β mRNA levels were also reduced ( 111 ). In vitro studies using animal macrophages have also confirmed similar immunosuppressive effects where the decrease in IL-6 and increase in IL-10 that follows treatment with amitriptyline, fluoxetine, and mianserin, suggests that such effects may be mediated by an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway ( 105 ). On the other hand, Munzer et al. ( 109 ) found that treatment in vitro of whole blood cultures with SSRIs and mirtazapine, a tetracyclic antidepressant (TeCA), had the opposite effect on the stimulated production of cytokines, with an increase in inflammatory markers including IL-1β, IL-6, and TNFα.

Efficacy prediction and immunomodulatory effect of therapies.

Summary of the interaction with the immune system of various antidepressant and anti-fatigue treatments, with the predictive efficacy of immune markers and their immunomodulatory effect listed. The experimental model used in each study (i.e., human vs. animal) is noted. SSRI, Selective serotonin reuptake inhibitor; SNRI, Serotonin–norepinephrine reuptake inhibitor; TCA, Tricyclic antidepressant; ECT, Electroconvulsive therapy; TNF, Tumor necrosis factor; sTNFR, Soluble tumor necrosis factor receptor; CRP, C-reactive protein; FGF, Fibroblast growth factor; IL, Interleukin; IP-10, Interferon gamma-induced protein 10; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; IFNγ, Interferon-γ; G-CSF, Granulocyte colony-stimulating factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; PBMC, Peripheral blood mononuclear cell; PDGF, Platelet-derived growth factor; VEGF, Vascular endothelial growth factor; RA, Rheumatoid arthritis .

Meta-analysis of human studies examining changes in a variety of serum cytokine levels showed that treatment with antidepressants lowered levels of IL-1β (the studies disagree on whether this is present only in SSRIs or also other antidepressants), IL-4, IL-6, and IL-10 ( 106 , 107 ). Other studies have also demonstrated that antidepressants have different immunomodulatory activities. Chen et al. ( 108 ) found that an SNRI (venlafaxine) had greater anti-inflammatory activity when compared to an SSRI (paroxetine). This study also showed that treatment with SSRIs significantly increase IL-6 levels and led to a non-significant increase in TNFα levels, contrary to previous findings. Human studies have also shown that treatment with psychotherapy has similar immunomodulatory effects to that of pharmaceutical therapies ( 39 ).Other recent studies have also looked at exercise, transcranial direct current stimulation (tDCS), and standard of care treatment and shown that the levels of a variety of circulating cytokines generally decrease following treatment, although there is no agreement on the correlation with improvement of depressive symptoms ( 100 , 118 , 127 ). Treatments such as electroconvulsive therapy (ECT) have somewhat similar effects on the immune system, although with different characteristics. Overall, ECT is associated with an initial spike of IL-1 and IL-6, with the levels of TNFα and IL-6 falling after treatment over the long term, though these results come from a limited number of studies ( 115 ). One study looked at the effect of ECT as an adjunctive treatment to antidepressants and found that while it did cause a significant decrease in IL-6, TNFα levels increased with treatment ( 116 ). ECT has also been shown to reverse the change in NK cell activity, which is decreased in depressed patients ( 17 , 117 ).

Studies have also illustrated that immune markers may be used to predict treatment efficacy. Lower baseline levels of proinflammatory cytokine predict better treatment response to TCAs, SSRIs, TeCAs, and ketamine, with responders having a significant decrease in these cytokine levels ( 110 , 112 , 128 ). However, Uher et al. ( 103 ) showed that baseline CRP levels predicted a differential treatment response to different antidepressants. Those patients with lower levels of CRP respond better to the SSRI escitalopram, while those with higher levels had a better response to nortriptyline, a TCA. These observations suggest that the clinical effects of SSRIs may be at least partially due to anti-inflammatory effects, which may not be the case for tricyclics. Higher IL-6, but not TNFα, levels in patients have also been associated with worse treatment efficacy of multiple different SSRI and SNRI treatments ( 101 ). On the other hand, Eller et al. ( 102 ) found that higher TNFα levels were associated with treatment non-response in patients being treated with escitalopram.

In antidepressant sleep deprivation therapy, higher IL-6 levels predicted worse treatment response in depressed patients with bipolar disorder, in agreement with previous studies on antidepressants ( 113 ). Lower TNFα levels at the first ECT have also shown to predict better treatment outcome ( 114 ). However, this correlation between higher inflammatory cytokine levels and worse treatment efficacy is not found in all treatments. It has been shown that higher serum proinflammatory cytokine levels, in this case TNFα, predicts a positive response to exercise therapy ( 118 ). The differences in predictive effects of circulating inflammatory cytokine levels regarding the efficacy of different treatments suggest that their mechanisms may differ, with anti-inflammatory effects being more important for some treatments, such as SSRIs, than others.

Few drugs are effective in treating fatigue; with even less studies done on the interaction those drugs have with the immune system. Amantadine is one drug that has been effective in patients with MS ( 129 ) but there is however a lack of studies on its immunomodulatory effect. A study on the effect of amantadine treatment in rats showed that while it enhanced the effect of fluoxetine when co-administered, it did not change the expression of IFNγ or IL-10 levels by splenocytes ( 119 ). Further studies will be required to examine whether its efficacy as a treatment for fatigue in MS patients is through effects on the immune system or through other pathways.

Effects on Depression and Fatigue by Treatment Targeting the Immune System

As the immune system plays a role in depression and fatigue, anti-inflammatory drugs and other treatments that change the immune system serve as a potential treatment option ( Table 1 ). An earlier meta-analysis of anti-inflammatory medications showed that there is a potential effect of COX-2 inhibitors on depression, with cytokine inhibitors having no significant effect. However, the authors were cautious in their conclusions due to the high heterogeneity of the studies ( 130 ). The use of non-steroidal anti-inflammatory drugs (NSAIDs) as an add-on to standard antidepressant therapy should however be done carefully due to the role innate immune response plays in normal neurological functions ( 23 ), and especially since the antidepressant effect of SSRIs can be attenuated by anti-inflammatory treatment ( 131 ). Minocycline, an antibiotic with immunomodulatory effects, has also been found to have antidepressant effects ( 120 , 132 ). One potential pathway for its action is through the rescuing effect on mouse hippocampal neural stem cell proliferation, which is suppressed by IFNα ( 133 ). A small meta-analysis of three Randomized Control Trials (RCTs) also suggest that it has a large treatment effect for depression and should be studied further ( 121 ). Given that minocycline may be effective in treating MS and lowering the risk of conversion from clinically isolated syndrome to MS ( 134 , 135 ), it could serve as an effective adjunctive treatment for patients with MS who are suffering from depression, though more studies will be required to support this hypothesis.

More recent studies suggest that the antidepressant effect of drugs targeting cytokines is significant ( 136 ). A meta-analysis by Kappelmann et al. ( 124 ) found that anti-cytokine drugs are significantly more effective than placebo in the treatment of depression. An RCT conducted by Raison et al. ( 122 ) examined the efficacy of TNFα antagonists in treatment-resistant depression and showed that, while no change was seen in the overall group, there was a significant effect in those with higher baseline CRP levels. The responders in this trial also had higher baseline plasma TNF and soluble TNF receptor levels and exhibited a significantly greater decrease in CRP than non-responders. This suggests that while the targeting of the immune system for treatment of depression may not work in all patients, it is a valid target for a subset of depressed patients whom inflammation may play a major role. The targeting of IL-6 by the IL-6 receptor antagonist tocilizumab has also been shown to improve depressive symptoms ( 124 ). Given that a third of depressed patients are treatment resistant even after four successive treatment steps ( 137 ), the exploration of the immune system as a treatment target is a legitimate area of interest, especially in those with higher baseline inflammation. Studies have also targeted the immune system through other means, including miR-155, a microRNA that is involved in inflammation and neuroplasticity ( 138 ). A study by Fonken et al. ( 139 ), found that mice with miR-155 KO in the hippocampus presented less depressive-like behavior and had significantly lower IL-6 and TNFα expression in this area. The increase in NFKBIA, a NF-κB inhibitor, expression in females in this study along with findings from in vitro studies ( 105 ) suggest that the NF-κB pathway's role in inflammatory activity may play a part in the development of depression, making it a potential treatment target to be explored. For treatment of fatigue, Elfferich et al. ( 123 ) showed that treatment with anti-TNFα drugs improved fatigue in sarcoidosis and had significantly better efficacy compared to both control and treatment with prednisone, a more general anti-inflammatory drug. A study in colorectal cancer patients found that prophylactic use of dexamethasone, which has anti-inflammatory effects, led to significantly lower levels of fatigue and better treatment tolerance compared to untreated control patients ( 125 ). Patients with RA who were treated with rituximab, an antibody which targets and depletes B cells, have also reported an improvement in fatigue after 1 year of treatment ( 126 ). On the other hand, a study examining chronic fatigue syndrome (CFS) showed that treating fatigue may not always be so straight forward ( 140 ). The authors targeted IL-1, which has been linked to CFS, using a receptor antagonist and found no significant effect on fatigue. The study did not measure cytokine levels in patients, so it is unclear whether patients with higher baseline IL-1 would have benefited more from the treatment, which would be inline with the results shown by Raison et al. ( 122 ).

Overall, there is strong evidence that changes in the immune system may be one of the pathways through which antidepressant therapies act. Many of the pharmaceutical antidepressant agents reduce inflammatory activation in immune cells and lower circulating inflammatory cytokine levels. Other treatments such as ECT, tDCS, psychotherapy, and exercise also result in decreases in inflammatory cytokine levels. Lower baseline inflammatory cytokine levels are also shown to predict better efficacy in most types of antidepressant treatments, except for exercise. Anti-inflammatory treatments have also been shown to be effective, with medications such as NSAIDS and anti-cytokine drugs having antidepressant effects. While the anti-fatigue drug amantadine has not been shown to have immunomodulatory effects, drugs targeting of TNFα and B cells both lead to decreased fatigue, suggesting potential targets for drug discovery for anti-fatigue therapies.

Future Directions

While there is consensus on the presence of a relationship between the immune system and symptoms like depression and fatigue, there are still some unanswered questions. One of these questions is the role this relationship plays in specific disorders such as MS, where the findings are less clear. In the case of some chronic diseases, such as MS, both depression and fatigue are hard to diagnose. This is due to the overlapping symptoms and the difficulty in determining what is caused by the disease itself (primary) and what is a result of a reaction to the diagnosis and disability induced by disease or the effects of its treatment (secondary). The complexity of depression and fatigue, both of which have multiple causes, makes studying these symptoms challenging. The above issues are further compounded in immune-related disorders, where there is a relative dearth of studies examining the immune-psychological relationship, making it more difficult to draw a conclusion from the contradictory findings ( 78 , 141 ). The contradictions in the results, the limited studies on this topic, along with the need to better understand the complex conditions that deeply affect the patient's suffering from depression and fatigue, demonstrates a vital need for further comprehensive studies.

Another difficulty when comparing studies on inflammation in depression and fatigue is the lack of comprehensive analysis of different cytokines in most studies. Many of the studies only look at a small subset of cytokines, and these subsets are often different between studies. This is less problematic in conditions where there is agreement on the affected markers, like cancer, but it can be an issue in diseases where there is no clear consensus, such as MS. In conditions with no clear consensus, studies should aim to measure a wider range of markers to make sure the potential changes are discovered, which would also help with reviewing results in the future and allowing for better conclusions to be made.

Studies should also explore aspects of the immune system beyond the often-measured level of circulatory cytokines and include the less common in vitro activation assays to explore other facets of the pathways. The study by Blank et al. ( 54 ) serves as a good example by examining changes in the whole pathway, covering immune, endothelial, and neural cells along with behavioral changes and treatment effects. Studies such as these paint a more comprehensive picture of how the immune system exerts its effect on the brain, which will also help to discover potential drug targets for treatment. Future studies should also explore potential drug targets based on known changes that result from depression and fatigue. This is important for discovering new antidepressant treatments but is even more important for treatment of fatigue, given that there are few existing treatments, often with unclear efficacy.

In addition, further studies should be done to examine whether previous immune activation due to sepsis or interferon treatments, for example, can independently prime the immune system. This would be similar to the two-hit hypothesis as suggested for some other psychological disorders ( 142 ), with the primed immune system making it easier for other biopsychosocial “hits” to result in increased susceptibility or increased severity of future depression and fatigue. While previous studies have shown that stress can prime the immune system and result in larger activated immune response ( 143 , 144 ), none have looked at the clean effect of intense immune activation, taking out the effect of the hypothalamic–pituitary–adrenal (HPA) axis, and the role it plays in future depression. This would be an interesting direction to explore as it would inform physicians to keep careful track of patients who have previously had strong activation of the immune system, since they may be more susceptible to suffering from depression and fatigue.

Depression and fatigue are symptoms that significantly impair those who suffer from them and it is therefore important to increase our understanding of both their etiology and the mechanisms involved. The described link between depression, fatigue and increased immune activation, the psychological effect of proinflammatory insults, and the treatment efficacy of anti-inflammatory medications, provide convincing evidence supporting the hypothesis that inflammation plays a role in the causation of some forms of depression and fatigue. However, in some diseases, such as MS, there is still conflicting evidence. For the disorders where the link is unclear such as immune-mediated diseases, a greater number of comprehensive, high quality studies are required to help better understand the immune-neuro-psychological interactions. Further exploration of this relationship between the immune and psychological systems will improve our understanding of the disease conditions and assist in designing better treatments to improve the quality of life of individuals affected by depression and fatigue.

Author Contributions

C-HL wrote the first draft of the manuscript. FG provided supervision and assisted with the writing and content of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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