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Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma

  • Antonio Inserra
  • Claudio Alberto Mastronardi
  • Geraint Rogers
  • Julio Licinio
  • Ma-Li Wong
Open Access
Article

Abstract

Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.

Keywords

Major depressive disorder MDD Inflammation Neuroinflammation Caspase 1 Inflammasome T-helper 1 (Th1) Interleukin 1 Inducible nitric oxide synthase Interferon gamma Gut microbiome 

Introduction

Major depressive disorder (MDD) is a psychiatric disorder with significant morbidity, mortality, disability, and economic burden worldwide [1, 2]. In addition to the psychosocial and psychophysical dysfunctions associated with MDD, several conditions are often comorbid, including but not limited to obesity, type-2 diabetes, heart conditions, autoimmune diseases, neurodegenerative disorders, cancer, and intestinal conditions [3, 4, 5, 6, 7]. Multiple hypotheses have been formulated attempting to describe the elusive pathophysiology of MDD, including the monoamine hypothesis, the neurotrophic hypothesis, the glutamate hypothesis, the cytokine (or macrophage) hypothesis, and the microbiota-inflammasome hypothesis [8, 9, 10, 11, 12, 13]. However, no single hypothesis seems to fully explain the onset, course, and remission of the disease. To complicate matters further, antidepressant drugs present numerous side effects and are effective only in a subset of patients [14, 15, 16]. Newer therapeutic strategies involve drugs acting on neuroplasticity-related pathways, gut microbiome modulation, and deep brain stimulation surgery [17, 18, 19]. Nevertheless, the quest for a better understanding of the molecular underpinnings of this disease represents an essential step in the identification of efficacious therapeutic strategies that could target the causal biological mechanisms of MDD.

Emerging evidence suggests that dysregulated neuro-immune pathways underlie depressive symptomatology in at least a subset of MDD patients [2, 20, 21, 22, 23, 24, 25]. Three crucial inter-linked networks seem to influence the bidirectional communication between the brain, the immune system, and the intestinal microbiome, namely (a) increased oxidative stress, driven by nitric oxide (NO) overproduction, (b) chronic inflammation, driven by caspase 1 (CASP1), and Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome over activation, and (c) central nervous system (CNS) T cell-helper 1 (Th1) lymphocyte infiltration, driven by interferon-gamma (IFNG). These three networks are strictly interlinked and present several levels of reciprocal regulation. For example, NO is a critical negative modulator of the NLRP3 inflammasome, while being necessary for IFNG-mediated suppression of interleukin-1 beta (IL1B) processing [26, 27]. Moreover, CASP1 regulates IFNG production via producing IL18, while IFNG modulates the CASP1 system [28]. Similarly, transcription of inducible nitric oxide synthase (NOS2) can be activated by IFNG [29]. Lastly, CASP1 is involved in the epigenetic regulation of NOS2 [30]. These multidirectional interactions suggest the importance of observing and therapeutically approaching these pathways as a whole rather than as insular entities. The possible involvement of these three systems in MDD is briefly summarized here and will be described in detail throughout this review.

Reactive oxygen species (ROS) are produced during cell metabolism, and are largely quenched by the endogenous antioxidant machinery [31]. However, excess of oxidative products can elicit oxidative stress and cause protein, lipid, and/or DNA damage [32]. Preclinical and clinical studies suggest that chronic stress exposure is associated with increased ROS production [33, 34, 35, 36, 37, 38, 39, 40]. One of the free radicals produced during psychological stress is NO, mainly by NOS2 [41]. Inflammatory factors play key roles in tissue repair and in defense against pathogens [42, 43]. However, pathological activation of inflammatory cascades caused by stress and other insults can alter brain function and increase the likelihood of developing MDD and comorbid conditions [44, 45, 46]. CASP1, a protease that in the NLRP3 inflammasome renders the mature forms of IL1B and IL18, is also activated by stress [47, 48]. It has been shown that reactive T cells infiltrate the brain where they produce pro-inflammatory cytokines in response to CNS antigens [49]. Lastly, IFNG is a powerful inducer of indoleamine 2,3-dioxygenase 1 (IDO1), which degrades tryptophan increasing kyneurine and quinolinic acid, leading to hyposerotonergia and hyperglutamatergia, involved in MDD [9, 50, 51].

Recently, the role of the gut microbiome in mental health and illness has come to the forefront in psychiatry [52, 53]. Increasing evidence suggests the existence of a gut-brain-axis, a communication network that integrates brain and gut function, which plays a fundamental role in health and disease [54]. Such communication occurs via the endocrine and immune systems, the vagus nerve, and the bacterial metabolome [55, 56, 57]. It is becoming clear that the gut-brain-axis is an entity directly involved in modulating stress systems like the hypothalamic-pituitary-adrenal (HPA) axis, via its effects on the immune and endocrine systems, which affect behavior and mood and that can lead to MDD [53, 58, 59]. Given its central role in modulating immune processes and brain function, and given that MDD is characterized by altered gut microbiome composition, consensus is growing that manipulating the gut microbiota could represent a therapeutic tool in the treatment of MDD [19, 60]. In this review, we will summarize the pre-clinical and clinical evidence supporting the involvement of CASP1, NOS2, and IFNG in the pathophysiological processes underlying depressive symptomatology.

Communication Between the Brain, the Immune System, and the Gut Microbiome

Although the CNS is considered to have its “own” immune system, independent from the peripheral immune system, it is accepted that the two constantly communicate and cooperate, that the CNS is involved in regulating immunity, and that immune responses in the periphery lead to behavioral changes [66, 67].

Stress-mediated upregulation of pro-inflammatory cytokines [such as IL1, IL6, tumor necrosis factor (TNF), and IFNG] leads to endocrine and neurochemical responses, such as sympathetic nervous system (SNS), hypothalamic-pituitary-adrenal (HPA) axis, and microglial activation. SNS stimulation triggers epinephrine and norepinephrine release in the locus coeruleus and adrenal medulla, which result in an upregulation of pro-inflammatory signaling. SNS activation in response to stress pushes the CNS to “steer” immunity towards pro-inflammatory and antiviral responses [23]. At the same time, norepinephrine modulates pro-inflammatory cytokines transcription via beta-adrenergic receptor stimulation [68].

This leads to HPA axis activation by hypothalamus-secreted corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). CRH stimulates adrenocorticotropic hormone (ACTH) release from the pituitary gland, which stimulates glucocorticoids release by the adrenal gland. Glucocorticoids interact with the glucocorticoid receptor (NR3C1) and the mineralocorticoid receptors (NR3C2), activating anti-inflammatory cascades and inhibiting Th1-driven pathways. This upregulates anti-inflammatory gene expression to avoid side effects [69, 70, 71, 72, 73]. The gut microbiome modulates HPA axis processes. In fact, germ-free rodents have greater plasma ACTH and corticosterone spikes compared to wild-type in response to stressors, while displaying altered anxiety-like behavior [74]. This exaggerated response can be reversed by early stage (but not later stage) recolonization with Bifidobacterium infantis [74]. Interestingly, the brain regions presenting the highest concentrations of pro-inflammatory cytokines are the prefrontal cortex, the hypothalamus, and the hippocampus, areas involved in cognition, mood, and antidepressant response [75, 76].

Increased concentrations of brain cytokines trigger the activation of microglia, immune cells inhabiting the brain parenchyma, representing chief innate immune cells in the brain [67, 77]. Depending on the temporal and qualitative cytokine profile, stress-induced microglial activation can either stimulate neuroprotection or neurodegeneration [78]. Not surprisingly, the gut microbiome modulates microglia homeostasis and maturation, while reduced gut microbiome complexity impairs microglia function [79]. Altogether, these stress-induced inflammatory events alter neurotransmitter systems, such as serotonin (5HT) and dopamine (DA), exacerbating depressive symptoms [80, 81]. Interestingly, the gut microbiome is also involved in neurotransmitter modulation, either via producing neurotransmitters, consuming them, or responding to them [82]. This raises the intriguing possibility that by altering gut microbiota composition, it might become possible to modulate neurotransmitter systems in pathological states, including MDD (Reviewed by [82]).

Glucocorticoids have the effect of restoring homeostasis [83]. However, in MDD, the HPA axis can become hyperactive. This phenomenon is underlined by increased cortisol, blunted ACTH response to CRH, glucocorticoid resistance, impairment in gluco- and mineral-corticoid signaling, and enlargement of the pituitary and adrenal glands [84, 85, 86, 87, 88]. Antidepressant drugs normalize the HPA axis and enhance the expression and function of corticosteroids [89, 90]. Peripheral cytokines can cross the blood-brain barrier (BBB) via (a) CNS lymphatic vessels, (b) active transport and a leaky or compromised BBB, (c) crossing at circumventricular organs, and (d) binding to receptors in the blood vessels that course through the brain [91, 92, 93, 94]. Moreover, cytokines can affect brain function indirectly, through vagal nerve activation or by binding to cell-surface proteins found in brain endothelial cells [91, 93, 95, 96].

Cytokines can be produced in the gut in response to bacterial virulence factors (such as LPS), and in response to bacterial translocation to physiologically sterile enteric compartments (“leaky gut”) [97]. It was proposed that the leaky gut phenomenon contributes to MDD [98]. In fact, stress is known to compromise gut epithelial barrier integrity, allowing gut bacteria to access the enteric nervous system and immune cells [99]. Intestinal inflammation is a major contributor to changes in gut microbiome composition and function that are associated with disease (Reviewed in [100]). IFNG triggers the production of hydrogen peroxide and the epithelial expression of NOS2, which elevates the concentration of NO, in turn favoring the expansion of facultative anaerobic clades and hindering enterocyte proliferation [100, 101]. The resulting inflamed intestine perpetuates the production of pro-inflammatory cytokines and inflammogenic microbial metabolites, which affect brain processes and precipitate MDD onset while increasing the likelihood of comorbid conditions [99, 102]. Lastly, cytokines are produced de novo in the brain in response to stress [103, 104, 105].

Psychoneuroimmune Interactions and the Cytokine Hypothesis of Depression

Psychoneuroimmunology studies the reciprocal interactions between behavioral traits and the immune system, mediated by the nervous and endocrine systems [106]. In MDD, increasing evidence suggests that the communication networks existing between the microbiota and the nervous, immune, and endocrine systems lie at the crossroads of psychosocial stress, onset of depressive symptomatology and antidepressant response [107]. Studies suggest anti-inflammatory, endocrine,- and entero-regulatory effects of antidepressants, antidepressant effects of anti-inflammatory medications, and differential responses to antidepressants driven by polymorphisms in inflammation-related genes [108, 109, 110, 111, 112]. With regard to the immune players of such communication, cytokines have gained increasing attention over the past 20 years. Cytokines are pleiotropic signaling molecules with immunomodulatory function expressed constitutively and on-demand in the periphery and in the CNS and have been associated in at least a subset of patients with onset, course, and severity of neuropsychiatric disorders, as well as with the response to therapeutic drugs [113, 114, 115, 116, 117, 118, 119, 120, 121, 122].

Exposure to psychological stressors primes the immune system towards the creation of a pro-inflammatory environment in the brain, a phenomena called sterile inflammation, which prepares the CNS and the body to trigger a potential full-blown immune response [123, 124]. While this program is essential for coping with the stressor and restoring homeostasis, it requires high amounts of energy and has collateral damage potential. In fact, repeated or chronic stress exposure results in a sustained inflammatory milieu in the brain which can lead to the development of MDD and comorbid illnesses [23, 125].

These lines of evidence led to the “cytokine hypothesis” (or “macrophage hypothesis”) of depression, which proposes that cytokines and an out-of-balance brain-immune communication are key MDD milestones [126, 127, 128, 129, 130]. This hypothesis is supported by mounting evidence: (a) illnesses characterized by chronic inflammatory responses (e.g., type-1 diabetes and systemic lupus erythematous) are associated with increased depression rates [4, 6], (b) administration of pro-inflammatory cytokines as a therapeutic strategy (e.g., IFNA administration in cancer and hepatitis-C) induces a dose-response depressive symptomatology and molecular features of MDD [131, 132, 133, 134, 135], and (c) pro-inflammatory cytokines administration in vivo induces sickness or depressive-like behavior [22, 136]. Lastly, polymorphisms in inflammation-related genes associate with increased MDD susceptibility and differential antidepressant response [25]. These layers of evidence suggest that neuroinflammation is involved in MDD, providing fertile ground to investigate diagnostic and therapeutic opportunities in neuro-immuno-psychiatry.

Major Depression and Dysregulated Inflammatory Pathways

Psychoneuroimmunology research has highlighted that at least a subgroup of MDD patients present with a systemic low-grade chronic inflammatory profile underlined by increased T cell, monocytic, microglial, and astrocytic activation [23, 24, 137, 138]. This is characterized by increased Th1 cytokines such as IL1, IL2, IL6, TNF, and IFNG, decreased Th2 cytokines such as IL4 and IL10, and decreased regulatory T cells [128, 139, 140, 141, 142, 143, 144]. The resulting skewed inflammatory balance triggers multi-level dysfunctions, such as metabolism, neurotransmission, gut microbiome, and neurogenesis alterations [137, 145, 146]. Accordingly, the neurotrophic hypothesis of depression suggests that MDD patients have inflammation-driven decreased neurogenesis, which leads to atrophy of brain areas such as the hippocampus and the prefrontal cortex [147, 148, 149, 150]. Not surprisingly, pro-inflammatory cytokines and increased glucocorticoids production downregulate neurotrophins (such as brain derived- and nerve-growth factor) and neurogenesis during and following stress, while antidepressants reverse such decreases [151, 152]. The gut microbiome is also involved in regulating neuroplasticity and neurogenesis; germ-free mice display altered neurogenesis and BDNF expression in the dentate gyrus, while antibiotic treatment impairs neurogenesis [74, 153, 154] (Fig. 1).
Fig. 1

Major depression and dysregulated inflammatory pathways

Cytokine Signaling and Nitrosative Stress

Oxidative stress is involved in MDD pathophysiology [155]. Stress exposure leads to ROS upregulation via cytokine-induced NOS2 induction, an event that heightens the overall oxidative stress, activating a feedback loop (co-activation state) that produces more cytokines [138]. Oxidative stress is characterized by the generation of ROS, which contributes to protein and DNA damage, and can result in irreversible brain function changes, leading to neurodegeneration and cognitive impairments [156]. Oxidative processes are gaining attention in psychiatry, since an expanding body of research suggests the involvement of these pathways in MDD [24, 40, 138, 157, 158, 159].

The involvement of oxidative and nitrosative stress in MDD is confirmed by the increased oxidative (such as NO, arachidonic acid, malondialdehyde, and 8-hydroxy-2-deoxyguanosine) and nitrosative (such as immunoglobulin (M IgM)- antibodies directed against phosphatidylitol and nitro-bovine serum albumin) stress markers in MDD patients, together with decreased levels of antioxidants (such as vitamins C and E) [160, 161, 162, 163, 164]. Interestingly, the concentration of oxidative stress markers correlates with depression severity and chronicity, as well as with antidepressant response [40, 138, 161, 165]. Accordingly, some antioxidant compounds have antidepressant properties, and antidepressants (such as paroxetine) partially reverse oxidative damage by enhancing the protective antioxidant status following stress [158, 166, 167, 168].

Of crucial importance for this work, the NO system is being investigated in MDD, because NO levels are increased in MDD and in animal models of stress, while NO inhibition has antidepressant effects (discussed in detail below) [37, 164, 169, 170, 171]. Increased levels of oxidative and nitrosative molecules can easily damage neurons, since they are particularly vulnerable to free radicals [172]. Moreover, the brain presents lower concentrations of antioxidants compared to other organs, making it more susceptible to free radicals [160]. Unsurprisingly, some areas (i.e., the subfields Cornu Ammonis (CA)1) and CA4) of the hippocampus (a brain region involved in mood regulation and adult neurogenesis) are the most sensitive to oxidative damage [24].

The Role of Caspase 1 in MDD

As mentioned above, stress triggers “sterile inflammation,” initiated by endogenous danger signal recognition, termed damage-associated molecular patterns (DAMPs), by glial cells, macrophages, and oligodendrocytes [124, 181, 182]. DAMPS are nuclear, cytosolic, mitochondrial, or extracellular molecules normally hidden from the immune system that upon activation are exposed and released in the extracellular space, where they stimulate an immune activation [124, 183]. In line with this understanding, increased levels of DAMPs have been found in rodent blood and hippocampus following stress exposure [103, 184].

Once released in the extracellular space, DAMPs function as alarm signals, alerting immune cells through pattern recognition receptors, to get ready for a potential full-blown immune response [182, 185, 186]. It has been hypothesized that such processes could represent an adaptive characteristic of the acute stress response; for example, if an animal were running away from a predator and were wounded during the chase, it might have better chances of surviving if its immune system were primed and ready to respond [187]. Another theory, one that places this mechanism in a modern context, suggests that such stress responses are activated when an individual is exposed to social evaluation, rejection, isolation, exclusion or conflict, possibly due to the potentially physically harmful significance of such social situations throughout history [188].

Together, DAMPs activation and release induce the transcriptional upregulation of a number of immune genes, such as IL1B, IL6, and TNF. This results in the creation of a pro-inflammatory milieu in the brain and periphery, and in the activation of the afferent nerves, which in turn leads to de novo production of pro-inflammatory cytokines in the brain and culminates with the onset of depressive-like behavior [22, 136, 189].

Further, DAMP activation results in the assembly of inflammasomes [186, 190] A peculiar role is played by the NLRP3 inflammasome, that consists of the NLRP3 protein, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and the cysteine-protease CASP1 [47]. Upon inflammasome assembly, the inactive procaspase 1 zymogen is proteolitically cleaved into the enzymatically active heterodimer [191, 192]. In turn, activated CASP1 cleaves pro-IL1B and pro-IL18 into their mature, releasable, bioactive isoforms [47, 193]. Increased circulating levels of IL1B activate the HPA axis, which increases glucocorticoids production. [72]

CASP1 and NLRP3 transcripts and their protein products are increased in peripheral blood mononuclear cells (PBMC) from MDD patients compared to controls, while antidepressants decrease such hyperactivity [61]. Similarly, IL1B and IL18 are increased in MDD, and their levels correlate with the severity of depression [61] (Table 1). Correspondingly, antidepressants decrease IL1B levels [109].
Table 1

Clinical evidence of CASP1 involvement in MDD

Clinical evidence

Reference

Increased CASP1 and NLRP3 transcription in PBMC (peripheral blood mononuclear cells) from MDD patients.

Increased NLRP3 protein levels in PBMC from MDD patients.

Increased IL1B and IL18 in serum from MDD patients which positively correlate with BDI (Beck Depression Inventory) score.

Antidepressant treatment decreased NLRP3 and CASP1 transcription in PBMC from MDD patients.

Antidepressant treatment decreased IL1B and IL18 in serum from MDD patients.

[61]

IL18 is increased in MDD patients.

[62, 63]

IL18 is increased in patients with panic disorder.

[63]

IL18 promoter variants (rs187238 and rs1946518) associate with higher IL18 transcription and increased susceptibility to MDD in patients exposed to stressful events.

[64]

Polymorphisms in the IL33 gene (rs11792633 and rs7044343) moderate the correlation between history of childhood abuse and recurrent depression in women.

[65]

Patients with recurrent depression have higher peripheral IL33

[65]

Casp1−/− mice display decreased depressive- and anxiety-like behaviors, while being protected by the exacerbation of depressive-like behavior following chronic stress [19, 173]. Similarly, minocycline-treated mice display resilience in developing depressive-like behavior following stress, and this effect is accompanied by the expansion of bacterial clades with anti-inflammatory properties, which could help explain minocycline’s antidepressant effects [19] (Table 2).
Table 2

Pre-clinical evidence of CASP1 involvement in animal models of MDD

Pre-clinical evidence

Reference

Chronic unpredictable mild stress (CUMS) increases PFC (prefrontal cortex) CASP1 activation and NLRP3 and IL1B transcription and protein level.

Antidepressant treatment decreases PFC NLRP3 protein level and IL1B transcription and protein level.

[173]

LPS-induced depressive-like behavior increases brain CASP1, NLRP3, and ASC transcription, and IL1B transcription and protein level.

Pre-treatment with an NLRP3 inhibitor (Ac -YVAD-CMK) ameliorates depressive-like behavior.

[174]

CUMS increases hippocampal and serum Il1b and increases hippocampal CASP1 activity and NLRP3 and ASC protein levels.

Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreases serum and hippocampal IL1B protein levels and decreases depressive-like behavior.

[175]

CASP1−/− mice display decreased depressive- and anxiety-like behaviors, while being protected by the exacerbation of depressive-like behavior following chronic stress.

The CASP1 inhibitor minocycline prevents the exacerbation of depressive-like behavior following stress.

Minocycline triggers the expansion of bacterial populations with anti-inflammatory effects.

[19]

CUMS increase hippocampal IL1B.

IL1R−/− mice do not display CUMS-induced behavioral or neuroendocrine changes.

IL1R−/− mice do not display CUMS-induced decreases in neurogenesis.

IL1B exogenous administration mimics CUMS-induced depressive-like symptoms.

[176]

Stress and Il1b administration suppress hippocampal cell proliferation.

IL1R1 blockade blocks the antineurogenic effects of stress.

[177]

IL18−/− mice display decreased depressive- and anxiety-like behaviors.

[178]

IL18 is involved in stress-induced microglial activation while contributing to dopaminergic degeneration.

[179, 180]

Acute stress increases IL33 expression in the paraventricular nucleus of the hypothalamus and in the prefrontal cortex.

[65]

CASP1−/− mice have the same behavioral and inflammatory responses to systemic lipopolysaccharide (LPS) administration as wild-type (wt) mice, but are resistant to the development of depressive-like behavior and to pro-inflammatory cytokines increase following intracerebroventricular LPS administration [194]. Moreover, CASP1−/− mice are resistant to lethal LPS doses and have decreased levels of inflammation-induced brain and systemic transcription [195, 196, 197]. Significantly for this review, CASP1 and the NLRP3 inflammasome are involved in the development of depressive-like behavior in stress models and are increased in MDD [61, 173]. At the same time, pathological shifts in gut microbiota composition and leaky gut trigger an increase in pro-inflammatory signaling, which increases the risk of developing depressive symptomatology and comorbid illnesses [198]. Such evidence has led to the formulation of the microbiota-inflammasome hypothesis of major depression and comorbid systemic illnesses [58]. This hypothesis suggests that pathological gut microbiome shifts upregulate pro-inflammatory pathways exacerbating depressive symptomatology and increasing the likelihood of developing comorbid conditions [58].

Interleukin-1B (IL1B)

IL1B binds to the interleukin-1 receptor (IL1R1), which results in the activation of many acute-phase inflammation genes, such as NOS2, IL6, and cyclooxygenase type 2 [192, 199]. Recently, it was suggested that NLRP3 inflammasome activation mediates IL1B orchestrated inflammation (that results in depressive-like behavior) in the prefrontal cortex following stress, and that fluoxetine reverses such changes [173, 175]. Accordingly, mice lacking the IL1 receptor are resistant to developing depressive-like behavior following chronic stress while being protected against the decrease in neurogenesis observed in wt mice following stress [176, 177].

Interleukin-1A (IL1A)

IL1A shares features with IL1B and is an equally potent pro-inflammatory cytokine [207]. However, IL1A also presents differences to IL1B. For example, unlike the IL1B precursor which is not active, both the pro-IL1A and the cleaved IL1A are active ligands of the IL1R1 [208]. Moreover, while IL1B is released, IL1A can be secreted or membrane-bound, although the factors that control such translocation have not been fully elucidated yet [207, 209]. Finally, while IL1B is produced on-demand in immune cells, IL1A is constitutively expressed in a variety of cell types but can be produced by immune cells in response to insults [210]. Interestingly, IL1A-mediated activation of p38-MAPK inhibits NR3C1 function, suggesting that the mechanism conferring glucocorticoid resistance in MDD could be associated with IL1A [211]. To the best of our knowledge, no studies have investigated anxiety- and depressive-like phenotypes in IL1A−/− mice.

Interleukin-18 (IL18)

IL18 is a prototypical Th1 cytokine for its ability to stimulate IFNG activity, and it is expressed in macrophages and dendritic cells [212]. Circulating IL18 increases during stress and in response to HPA axis activation [213]. IL18 binds to the IL18 receptor (IL18R) activating p38-MAPK, c-Jun N-terminal kinase, and NFKB1 cascades, which potentiate antimicrobial and antiviral immunity [214, 215]. Although IL18 is known for its ability to promote both Th1- and Th2-related inflammatory responses, its predominant role in enhancing Th1 activity makes this cytokine a candidate therapeutic target in Th1-related inflammatory and autoimmune diseases, including MDD [212].

IL18 is increased in MDD and in panic disorder [62, 63]. IL18 gene promoter variants (rs187238 and rs1946518) associate with higher IL18 transcription and increased MDD susceptibility in patients exposed to stressful events. IL18−/− mice have decreased IFNG production and impaired natural killer cell activity and abnormal Th1 responses [216]. Moreover, IL18−/− mice display decreased depressive- and anxiety-like behavior, as well as gene expression changes across various brain regions [178, 217]. In addition, immobilization stress in mice induces pro-IL18 via ACTH and a superoxide-activated CASP1 pathway [218]. Given that IL6 is not induced in response to stress in IL18−/− mice, it seems that IL18 mediates stress-induced IL6 upregulation [218]. Lastly, IL18 is involved in stress-induced microglial activation in rodents while contributing to dopaminergic degeneration [179, 180].

Interleukin-33 (IL33)

IL33 has alarmin and transcription factor roles and triggers predominantly Th2 responses (such as the induction of IL4, IL5, IL13, and anti-inflammatory gene expression) [221]. Like other members of the IL1 family, IL33 can be beneficial or detrimental, depending on its spatio-temporal expression. IL33 is constitutively expressed and localized in the cytoplasm. However, if a barrier is breached and IL33 is released from destroyed cells, it acts as an alarmin upon binding the IL33 receptor (ST2) [222]. The signaling cascade in response to ST2 activation modulates hundreds of genes with a pattern that resembles that of IL1R1 activation [223].

Two single nucleotide polymorphisms in the IL33 gene (rs11792633 and rs7044343) moderate the correlation between history of childhood abuse and recurrent depression in women [65]. Moreover, patients with a history of recurrent depression have greater peripheral levels of IL33 and IL1B [65]. Finally, IL33 is expressed in the paraventricular nucleus of the hypothalamus and in the prefrontal cortex of rats exposed to acute stress, suggesting that stress induces IL33 expression in those brain regions [65].

The Role of Inducible Nitric Oxide Synthase in MDD

NO is a small intercellular and intracellular signaling molecule with a very short half-life (3–6 s) that freely diffuses across cell membranes. NO plays important roles in the brain modulating pathways such as neurogenesis, neurotransmission, synaptic plasticity, learning, and pain [224]. NO also regulates emotional and cognitive processes, suggesting that it could be involved in the etiology of MDD and anxiety disorders [225]. Three isoforms of the NOS enzyme produce NO: NOS2, neuronal (NOS1), and endothelial (NOS3), all of which have specific spatio-temporal patterns of regulation. In this review, we will focus on the inducible isoform since it is considered the most relevant to MDD.

Over the past two decades, several lines of evidence have brought NO and specifically the NOS2 isoform to the forefront in psychiatry: (a) the levels of NO and its metabolites are increased in MDD patients and suicide attempters compared to controls [171, 200, 201], (b) NOS2 transcription is increased in the peripheral blood of patients with recurrent depressive disorder [202], (c) a polymorphism (-1026C/A) in the NOS2 promoter associates with recurrent depressive disorder risk [203], (d) IgM against NO adducts are elevated in MDD patients, suggesting that the protein damage created by NO results in the formation of immunogenic peptides, that in turn activate an autoimmune-like response [204, 205], (e) the selective serotonin reuptake inhibitor paroxetine is a NOS2 inhibitor [206, 226], (f) adjuvant NOS2 inhibition enhances the efficacy of serotonergic antidepressants [169], and (g) NOS2 is increased in the hippocampus and cerebral cortex in mice following stress, and NOS2 inhibition results in antidepressant-like effects in rodents [38, 219, 220] (Tables 3-4).
Table 3

Clinical evidence of NOS2 involvement in MDD

Clinical evidence

Reference

Increased plasma nitric oxide (NO) metabolites in suicide attempters.

Increased plasma NO metabolites in depressed suicide attempters.

[171]

Increased plasma NO metabolites in suicide attempters.

Higher plasma NO levels were related to lower suicide lethality and lower depression severity.

[200]

Increased plasma nitrate concentration in MDD patients.

[201]

Increased NOS2 transcription in peripheral blood of MDD patients.

[202]

The polymorphism (-1026C/A) in the NOS2 promoter is associated with the risk of recurrent depressive disorder.

[203]

IgM levels against NO adducts are elevated in MDD patients, suggesting an autoimmune-like response.

[204, 205]

The antidepressant paroxetine is a NOS2 inhibitor.

[206]

Table 4

Pre-clinical evidence of NOS2 involvement in animal models of MDD

Pre-clinical evidence

Reference

NOS2 inhibitors augment the efficacy of serotonin reuptake inhibitors in the forced swim test.

[169]

NOS2 is increased in the hippocampus and cerebral cortex following stress.

[38]

NOS2 inhibition results in antidepressant-like effects in rodents.

[219]

The dopamine reuptake inhibitor bupropion modulates the NO system.

[220]

The architecture of the NOS2 promoter region suggests that this gene has a tight and complex pattern of transcriptional control since it is rich in positive and negative regulatory regions, and it is responsive to many transcription factors, cytokines, and bacterial by-products [29]. NOS2 is synthesized on-demand in macrophages and microglia [227]. In fact, whereas there is no detectable physiological NOS2 expression in the brain, a profound transcriptional upregulation of the NOS2 gene can be observed in response to traumatic events such as ischemia and systemic inflammation, most likely through activation of the NOS2 promoter by inflammation-related molecules [29, 39, 196, 228, 229]. Following induction, NOS2 produces NO continuously until the proteasome degradation pathway inactivates the enzyme [230].

Several studies have targeted the NO system in pre-clinical MDD research, yielding promising results. For example, NO decreases norepinephrine production, decreases nitrate and nitrite levels in the hippocampus and cerebral cortex, and decreases serotonin turnover in the frontal cortex [231, 232, 233]. Moreover, NO inhibits the dopamine transporter, indirectly increasing the availability of inter-synaptic dopamine [234]. Finally, several molecules such as bupropion (a norepinephrine-dopamine reuptake inhibitor), venlafaxine (a serotonin-norepinephrine reuptake inhibitor), mementine (an NMDA receptor antagonist), and berberine (a plant alkaloid), all of which produce antidepressant-like effects, modulate this signaling pathway [235].

It is accepted that anaerobic bacteria in the gut prevent the expansion of facultative anaerobic bacteria, at least partially by limiting the host-mediated production of oxygen and nitrate [236]. Antibiotic-mediated disruption of the gut microbiota increases the production of host nitrate in the gut [237]. This allows an expansion of the facultative anaerobic Enterobacteriaceae, which includes potentially pathogenic gram-negative bacteria, such as Escherichia coli (this effect is likely not to be limited to E. coli, although the latter has been the focus of investigation to date). These bacteria produce the virulence molecule LPS, which triggers depressive-like behavior and increases serotonin degradation in the brain [237, 238]. This alteration is mediated by NOS2; therefore, its inhibition prevents E. coli overgrowth [237]. Therefore, rectifying aberrant NO signaling could have a therapeutic role in altered gut microbiology-induced depressive symptoms [239]. Accordingly, stimulation of colonic epithelial cancer cells by IFNG induces NOS2-mediated NO production, while butyrate (one of the main anti-inflammatory short chain fatty acids (SCFAs)) blunts NO production [237]. This result suggests that a diet rich in substrates for SCFAs production could have antidepressant-like effects via its repercussions on gut microbiome composition and inflammatory processes. Together, these findings suggest that modulation of the NO system could represent a useful approach in treating MDD and in keeping of a healthy gut microbiome.

The Role of Interferon-Gamma in MDD

IFNG is a pleiotropic soluble cytokine which orchestrates cellular programs via transcriptional and translational gene control. IFNG is produced by immune cells such as lymphocytes, cytotoxic lymphocytes, B cells, and antigen-presenting cells [240, 241]. The IFNG receptor (IFNGR) is expressed on almost all cell types, and its activation triggers the janus kinase 1 and 2 (JAK1/2) signal transducer and activator of transcription 1 (STAT1) pathway, as well as additional pathways, such as the extracellular-signal-regulated-kinase 1/2 (ERK1/2) [242, 243]. Activation of the IFNGR results in the transcription of genes with IFNG-stimulated response elements (ISREs) within their promoter region until STAT1 dissociates following complete dephosphorylation within 1–2 h [244, 245]. The genes transcribed in response to IFNGR activation are at least 200, together with many micro RNAs and long non-coding RNAs [246] (for a database see [247]). At the same time, after IFNGR stimulation, the secondary transcription factors IRF1, IRF2, and interferon consensus sequence binding protein are upregulated. This in turn results in the transcriptional induction of a subset of inflammatory-related genes such as NOS2 (stimulated by IRF1) and guanylate-binding protein. Finally, IFNG can activate and be activated by CASP [248, 249, 250, 251].

Ex vivo PBMC from MDD patients display increased IFNG and neopterin production upon stimulation, as well as decreased tryptophan bioavailability [252]. Nevertheless, IFNG transcriptional levels (together with those of TNF) in patients with multiple sclerosis correlate with the severity of the depressive symptomatology during flare-ups [253]. At the same time, most categories of antidepressants suppress the IFNG/IL10 ratio through suppressing IFNG and stimulating IL10 [254, 255]. These findings (Table 5) suggest that MDD patients have increased systemic IFNG and neopterin production by activated T cells and macrophages. This could be responsible for an upregulation of the enzyme IDO1 (since the latter presents 2 ISREs at the promoter region that lead to maximum promoter activity) and consequent tryptophan depletion through upregulation of the kyneurine/tryptophan pathway, events that decrease serotonin availability and increase the toxic metabolite kyneurine [252, 258, 259, 260]. Accordingly, a polymorphism (CA repeat, rs3138557) in the IFNG gene correlates with lower serum tryptophan and 5-hydroxindolacetic acid (the main metabolite of serotonin) and higher levels of kyneurine, suggesting that carriers of the CA allele might be more susceptible to developing MDD [256]. Similarly, the presence of the high producer T allele +874(T/A) polymorphism (rs2430561) associates with increased IDO1 activity [257]. Interestingly, IFNG signaling drives Th1 development [261, 262]; therefore, early increased signaling of IFNG by traumatic events could be involved in the Th1/Th2 shift towards Th1 in MDD [141].
Table 5

Clinical evidence of IFNG involvement in MDD

Clinical evidence

Reference

Ex vivo PBMC from MDD patients display increased IFNG production upon stimulation.

[252]

Transcriptional levels of IFNG correlate with depressive symptomatology in multiple sclerosis patients.

[253]

The antidepressants clomipramine, sertraline, and trazodone suppress IFNG production.

[254, 255]

A polymorphism in the IFNG gene (CA repeat, rs3138557) correlates with lower serum tryptophan and higher kyneurine increasing MDD likelihood.

[256]

The high producer T allele + 874(T/A) polymorphism (rs2430561) in the IFNG gene has been associated with increased IDO1 activity and increased MDD likelihood.

[257]

IFNG−/− mice do not show developmental defects but present compromised immune responses and increased susceptibility to infections [263]. With regard to their behavior, IFNG/− mice display decreased anxiety- and depressive-like behaviors as well as heightened emotionality in several paradigms [264, 265, 266]. These behaviors are underlined by (a) increased serotonergic and noradrenergic activity (i.e., greater metabolite accumulation) in the central amygdaloid nucleus, together with (b) increased baseline plasma corticosterone, (c) decreased neurogenesis in the hippocampus, and (d) decreased levels of nerve-growth factor in the prefrontal cortex, suggesting that IFNG modulates anxiety and depressive states and is involved in CNS plasticity [264, 265]. On the other hand, while IFNG deficiency does not confer resistance to a chronic stress regimen in mice, it attenuates monoamine, corticoid, and cytokine alterations in response to stressors [264] (Table 6).
Table 6

Pre-clinical evidence of IFNG involvement in animal models of MDD

Pre-clinical evidence

Reference

IFNG/− mice display decreased anxiety- and depressive-like behaviors as well as heightened emotionality.

[264, 265, 266]

IFNG/− mice display increased serotonergic and noradrenergic metabolite accumulation.

[264, 265]

IFNG/− mice display increased plasma corticosterone levels.

[264, 265]

IFNG/− mice display decreased hippocampal neurogenesis.

[264, 265]

IFNG/− mice display decreased levels of nerve growth factor in the prefrontal cortex.

[264, 265]

IFNG/− mice have attenuated monoamine, corticoid, and cytokine alterations in response to stressors.

[264]

IFNG signaling promotes leaky gut and bacterial translocation. In fact, in vitro experiments have highlighted that low-dose IFNG dramatically increases the translocation of opportunistic pathogens, and high-doses disrupt tight junctions [267]. Lastly, IFNG levels affect the representation of specific bacterial species while being up- or downregulated by specific commensals [97]. For example, the degradation of tryptophan to the metabolite tryptophol inhibits IFNG production, while IFNG levels dictate the presence and expansion of specific bacterial taxa [97]. Given this evidence for an involvement of IFNG in pathways relevant to depressive symptoms and gut dysbiosis, targeting IFNG and/or its receptor could hold potential in the quest for novel MDD therapies.

Conclusions and Future Directions

Convergent pre-clinical and clinical evidence points towards an involvement of central and peripheral inflammatory pathways and the gut microbiome in the response to psychological stressors and in the onset, treatment, and remission of MDD. Future randomized controlled trials should investigate the safety and efficacy of decreasing CASP1-, NOS2,- and IFNG-mediated pathways in MDD patients. Reduced activity of those pro-inflammatory mediators could be achieved via pharmacological inhibition or gut microbiome manipulation. The latter approach can involve diet, probiotics supplementation, and fecal microbiota transplantation. This could lead to the development of novel antidepressant strategies acting upon the dysregulated inflammatory milieu observed in MDD. Because inhibiting such pathways might hinder physiological immune processes, particular care should be taken when developing immunomodulatory and gut microbiota-directed therapies.

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet 349(9064):1498–1504.  https://doi.org/10.1016/S0140-6736(96)07492-2 CrossRefGoogle Scholar
  2. 2.
    Maes M, Leonard B, Fernandez A, Kubera M, Nowak G, Veerhuis R, Gardner A, Ruckoanich P et al (2011) (Neuro)inflammation and neuroprogression as new pathways and drug targets in depression: From antioxidants to kinase inhibitors. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):659–663.  https://doi.org/10.1016/j.pnpbp.2011.02.019 CrossRefGoogle Scholar
  3. 3.
    Levitan RD, Davis C, Kaplan AS, Arenovich T, Phillips DI, Ravindran AV (2012) Obesity comorbidity in unipolar major depressive disorder: refining the core phenotype. J Clin Psychiatry 73(8):1119–1124.  https://doi.org/10.4088/JCP.11m07394 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Katon WJ (2008) The comorbidity of diabetes mellitus and depression. Am J Med 121(11 Suppl 2):S8–S15.  https://doi.org/10.1016/j.amjmed.2008.09.008 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Halaris A (2009) Comorbidity between depression and cardiovascular disease. Int Angiol 28(2):92–99PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kayser MS, Dalmau J (2011) The emerging link between autoimmune disorders and neuropsychiatric disease. J Neuropsychiatry Clin Neurosci 23(1):90–97.  https://doi.org/10.1176/appi.neuropsych.23.1.90 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Brintzenhofe-Szoc KM, Levin TT, Li Y, Kissane DW, Zabora JR (2009) Mixed anxiety/depression symptoms in a large cancer cohort: prevalence by cancer type. Psychosomatics 50(4):383–391.  https://doi.org/10.1176/appi.psy.50.4.383 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61(5–6):519–525CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Muller N, Schwarz MJ (2007) The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 12(11):988–1000.  https://doi.org/10.1038/sj.mp.4002006 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lesch KP, Beckmann H (1990) The serotonin hypothesis of depression. Fortschr Neurol Psychiatr 58(11):427–438.  https://doi.org/10.1055/s-2007-1001206 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62(1):63–77.  https://doi.org/10.1016/j.neuropharm.2011.07.036 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127.  https://doi.org/10.1016/j.biopsych.2006.02.013 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Inserra A, Rogers GB, Licinio J, Wong ML (2018) The microbiota-Inflammasome hypothesis of major depression. Bioessays 40(9):e1800027.  https://doi.org/10.1002/bies.201800027 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM et al (2006) Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354(12):1231–1242.  https://doi.org/10.1056/NEJMoa052963 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163(11):1905–1917.  https://doi.org/10.1176/ajp.2006.163.11.1905 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163(1):28–40.  https://doi.org/10.1176/appi.ajp.163.1.28 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J (2018) Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry 23(5):1094–1112.  https://doi.org/10.1038/mp.2018.2 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Huang YJ, Lane HY, Lin CH (2017) New treatment strategies of depression: based on mechanisms related to neuroplasticity. Neural Plast 2017:4605971.  https://doi.org/10.1155/2017/4605971 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S (2016) From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 21(6):738–748.  https://doi.org/10.1038/mp.2016.50 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P et al (2012) Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry 2:e79.  https://doi.org/10.1038/tp.2012.8 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Maes M (2008) The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29(3):287–291PubMedPubMedCentralGoogle Scholar
  22. 22.
    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56.  https://doi.org/10.1038/nrn2297 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65(9):732–741.  https://doi.org/10.1016/j.biopsych.2008.11.029 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36(2):764–785.  https://doi.org/10.1016/j.neubiorev.2011.12.005 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wong ML, Dong C, Maestre-Mesa J, Licinio J (2008) Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13(8):800–812.  https://doi.org/10.1038/mp.2008.59 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM (2013) Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nat Immunol 14(1):52–60.  https://doi.org/10.1038/ni.2474 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mao K, Chen S, Chen M, Ma Y, Wang Y, Huang B, He Z, Zeng Y et al (2013) Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Cell Res 23(2):201–212.  https://doi.org/10.1038/cr.2013.6 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L et al (1997) Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386(6625):619–623.  https://doi.org/10.1038/386619a0 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Xie QW, Whisnant R, Nathan C (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med 177(6):1779–1784CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Buzzo CL, Medina T, Branco LM, Lage SL, Ferreira LC, Amarante-Mendes GP, Hottiger MO, De Carvalho DD et al (2017) Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage. Sci Rep 7:41686.  https://doi.org/10.1038/srep41686 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Karihtala P, Soini Y (2007) Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS 115(2):81–103.  https://doi.org/10.1111/j.1600-0463.2007.apm_514.x CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Liu J, Wang X, Shigenaga MK, Yeo HC, Mori A, Ames BN (1996) Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats. FASEB J 10(13):1532–1538CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Patki G, Solanki N, Atrooz F, Allam F, Salim S (2013) Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 1539:73–86.  https://doi.org/10.1016/j.brainres.2013.09.033 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Miyashita T, Yamaguchi T, Motoyama K, Unno K, Nakano Y, Shimoi K (2006) Social stress increases biopyrrins, oxidative metabolites of bilirubin, in mouse urine. Biochem Biophys Res Commun 349(2):775–780.  https://doi.org/10.1016/j.bbrc.2006.08.098 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shao Y, Yan G, Xuan Y, Peng H, Huang QJ, Wu R, Xu H (2015) Chronic social isolation decreases glutamate and glutamine levels and induces oxidative stress in the rat hippocampus. Behav Brain Res 282:201–208.  https://doi.org/10.1016/j.bbr.2015.01.005 CrossRefGoogle Scholar
  36. 36.
    Noh SR, Cheong HK, Ha M, Eom SY, Kim H, Choi YH, Paek D (2015) Oxidative stress biomarkers in long-term participants in clean-up work after the Hebei Spirit oil spill. Sci Total Environ 515-516:207–214.  https://doi.org/10.1016/j.scitotenv.2015.02.039 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Fernandez AP, Rodrigo J, Bosca L, Leza JC (2000) Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex. J Neurochem 74(2):785–791CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Bosca L, Leza JC (2001) Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem 76(2):532–538CrossRefPubMedCentralGoogle Scholar
  39. 39.
    Yoshida T, Waeber C, Huang Z, Moskowitz MA (1995) Induction of nitric oxide synthase activity in rodent brain following middle cerebral artery occlusion. Neurosci Lett 194(3):214–218CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Chung CP, Schmidt D, Stein CM, Morrow JD, Salomon RM (2013) Increased oxidative stress in patients with depression and its relationship to treatment. Psychiatry Res 206(2–3):213–216.  https://doi.org/10.1016/j.psychres.2012.10.018 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Peng YL, Liu YN, Liu L, Wang X, Jiang CL, Wang YX (2012) Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress. J Neuroinflammation 9:75.  https://doi.org/10.1186/1742-2094-9-75 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240–273, table of contents.  https://doi.org/10.1128/CMR.00046-08 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Joffre O, Nolte MA, Sporri R, Reis e Sousa C (2009) Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev 227(1):234–247.  https://doi.org/10.1111/j.1600-065X.2008.00718.x CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rohleder N (2014) Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med 76(3):181–189.  https://doi.org/10.1097/PSY.0000000000000049 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Onat A, Can G (2014) Enhanced proinflammatory state and autoimmune activation: A breakthrough to understanding chronic diseases. Curr Pharm Des 20(4):575–584CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Lasselin J, Capuron L (2014) Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation 21(2–3):95–101.  https://doi.org/10.1159/000356535 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10(3):241–247.  https://doi.org/10.1038/ni.1703 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13(6):397–411.  https://doi.org/10.1038/nri3452 CrossRefGoogle Scholar
  49. 49.
    Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393–407.  https://doi.org/10.1038/nri2550 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5(11):2516–2522CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Wirleitner B, Neurauter G, Schrocksnadel K, Frick B, Fuchs D (2003) Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem 10(16):1581–1591CrossRefPubMedCentralGoogle Scholar
  52. 52.
    Deans E (2016) Microbiome and mental health in the modern environment. J Physiol Anthropol 36(1):1.  https://doi.org/10.1186/s40101-016-0101-y CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13(10):701–712.  https://doi.org/10.1038/nrn3346 CrossRefGoogle Scholar
  54. 54.
    Grenham S, Clarke G, Cryan JF, Dinan TG (2011) Brain-gut-microbe communication in health and disease. Front Physiol 2:94.  https://doi.org/10.3389/fphys.2011.00094 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336(6086):1262–1267.  https://doi.org/10.1126/science.1223813 CrossRefPubMedGoogle Scholar
  56. 56.
    El Aidy S, Dinan TG, Cryan JF (2014) Immune modulation of the brain-gut-microbe axis. Front Microbiol 5:146.  https://doi.org/10.3389/fmicb.2014.00146 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Forsythe P, Bienenstock J, Kunze WA (2014) Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol 817:115–133.  https://doi.org/10.1007/978-1-4939-0897-4_5 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Inserra A, Rogers GB, Licinio J, Wong ML (2018) The microbiota-inflammasome hypothesis of major depression. Bioessays 40(9):e1800027.  https://doi.org/10.1002/bies.201800027 CrossRefGoogle Scholar
  59. 59.
    Dinan TG, Cryan JF (2013) Melancholic microbes: a link between gut microbiota and depression? Neurogastroenterol Motil 25(9):713–719.  https://doi.org/10.1111/nmo.12198 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ianiro G, Bibbo S, Gasbarrini A, Cammarota G (2014) Therapeutic modulation of gut microbiota: current clinical applications and future perspectives. Curr Drug Targets 15(8):762–770CrossRefPubMedCentralGoogle Scholar
  61. 61.
    Alcocer-Gomez E, de Miguel M, Casas-Barquero N, Nunez-Vasco J, Sanchez-Alcazar JA, Fernandez-Rodriguez A, Cordero MD (2014) NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav Immun 36:111–117.  https://doi.org/10.1016/j.bbi.2013.10.017 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Prossin AR, Koch AE, Campbell PL, McInnis MG, Zalcman SS, Zubieta JK (2011) Association of plasma interleukin-18 levels with emotion regulation and mu-opioid neurotransmitter function in major depression and healthy volunteers. Biol Psychiatry 69(8):808–812.  https://doi.org/10.1016/j.biopsych.2010.10.014 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kokai M, Kashiwamura S, Okamura H, Ohara K, Morita Y (2002) Plasma interleukin-18 levels in patients with psychiatric disorders. J Immunother 25(Suppl 1):S68–S71CrossRefPubMedCentralGoogle Scholar
  64. 64.
    Haastrup E, Bukh JD, Bock C, Vinberg M, Thorner LW, Hansen T, Werge T, Kessing LV et al (2012) Promoter variants in IL18 are associated with onset of depression in patients previously exposed to stressful-life events. J Affect Disord 136(1–2):134–138.  https://doi.org/10.1016/j.jad.2011.08.025 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kudinova AY, Deak T, Hueston CM, McGeary JE, Knopik VS, Palmer RH, Gibb BE (2016) Cross-species evidence for the role of interleukin-33 in depression risk. J Abnorm Psychol 125(4):482–494.  https://doi.org/10.1037/abn0000158 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Fung A, Vizcaychipi M, Lloyd D, Wan Y, Ma D (2012) Central nervous system inflammation in disease related conditions: mechanistic prospects. Brain Res 1446:144–155.  https://doi.org/10.1016/j.brainres.2012.01.061 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6(4):318–328.  https://doi.org/10.1038/nri1810 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Cole SW (2010) Elevating the perspective on human stress genomics. Psychoneuroendocrinology 35(7):955–962.  https://doi.org/10.1016/j.psyneuen.2010.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER, Lightman SL, Lupien SJ, Roozendaal B et al (2006) Do corticosteroids damage the brain? J Neuroendocrinol 18(6):393–411.  https://doi.org/10.1111/j.1365-2826.2006.01429.x CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hayashi R, Wada H, Ito K, Adcock IM (2004) Effects of glucocorticoids on gene transcription. Eur J Pharmacol 500(1–3):51–62.  https://doi.org/10.1016/j.ejphar.2004.07.011 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Turnbull AV, Rivier C (1995) Regulation of the HPA axis by cytokines. Brain Behav Immun 9(4):253–275.  https://doi.org/10.1006/brbi.1995.1026 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Dunn AJ (2000) Cytokine activation of the HPA axis. Ann N Y Acad Sci 917:608–617CrossRefPubMedCentralGoogle Scholar
  73. 73.
    Coutinho AE, Chapman KE (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335(1):2–13.  https://doi.org/10.1016/j.mce.2010.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275.  https://doi.org/10.1113/jphysiol.2004.063388 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Borsini A, Zunszain PA, Thuret S, Pariante CM (2015) The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci 38(3):145–157.  https://doi.org/10.1016/j.tins.2014.12.006 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229.  https://doi.org/10.1016/j.neuroscience.2013.04.060 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, Ramirez-Chan K, Wang Y et al (2017) Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry.  https://doi.org/10.1038/mp.2017.64 CrossRefPubMedCentralGoogle Scholar
  78. 78.
    Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3(3):216–227.  https://doi.org/10.1038/nrn752 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18(7):965–977.  https://doi.org/10.1038/nn.4030 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Kohler S, Cierpinsky K, Kronenberg G, Adli M (2016) The serotonergic system in the neurobiology of depression: relevance for novel antidepressants. J Psychopharmacol 30(1):13–22.  https://doi.org/10.1177/0269881115609072 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59(12):1151–1159.  https://doi.org/10.1016/j.biopsych.2005.09.018 CrossRefGoogle Scholar
  82. 82.
    Strandwitz P (2018) Neurotransmitter modulation by the gut microbiota. Brain Res 1693(Pt B):128–133.  https://doi.org/10.1016/j.brainres.2018.03.015 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Herman JP, McKlveen JM, Solomon MB, Carvalho-Netto E, Myers B (2012) Neural regulation of the stress response: glucocorticoid feedback mechanisms. Braz J Med Biol Res 45(4):292–298CrossRefPubMedCentralGoogle Scholar
  84. 84.
    Gold PW, Goodwin FK, Chrousos GP (1988) Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (1). N Engl J Med 319(6):348–353.  https://doi.org/10.1056/NEJM198808113190606 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Holsboer F, Barden N (1996) Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 17(2):187–205.  https://doi.org/10.1210/edrv-17-2-187 CrossRefGoogle Scholar
  86. 86.
    Nemeroff CB (1996) The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1(4):336–342PubMedPubMedCentralGoogle Scholar
  87. 87.
    Owens MJ, Nemeroff CB (1993) The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies. CIBA Found Symp 172:296–308 discussion 308-216PubMedPubMedCentralGoogle Scholar
  88. 88.
    Pace TW, Miller AH (2009) Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann N Y Acad Sci 1179:86–105.  https://doi.org/10.1111/j.1749-6632.2009.04984.x CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Pariante CM, Miller AH (2001) Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment. Biol Psychiatry 49(5):391–404CrossRefPubMedCentralGoogle Scholar
  90. 90.
    Fitzgerald P, O'Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG (2006) Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol Med 36(1):37–43.  https://doi.org/10.1017/S003329170500632X CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Blatteis CM (1992) Role of the OVLT in the febrile response to circulating pyrogens. Prog Brain Res 91:409–412CrossRefPubMedCentralGoogle Scholar
  92. 92.
    Banks WA (2005) Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11(8):973–984CrossRefPubMedCentralGoogle Scholar
  93. 93.
    Maier SF, Watkins LR (2003) Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment. Brain Behav Immun 17(Suppl 1):S125–S131CrossRefPubMedCentralGoogle Scholar
  94. 94.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341.  https://doi.org/10.1038/nature14432 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Rivest S (1999) What is the cellular source of prostaglandins in the brain in response to systemic inflammation? Facts and controversies. Mol Psychiatry 4(6):500–507CrossRefPubMedCentralGoogle Scholar
  96. 96.
    Maier SF, Goehler LE, Fleshner M, Watkins LR (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289–300CrossRefPubMedCentralGoogle Scholar
  97. 97.
    Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, Ter Horst R, Jansen T et al (2016) Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167(4):1125–1136.e28.  https://doi.org/10.1016/j.cell.2016.10.020 CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127(5):344–354.  https://doi.org/10.1111/j.1600-0447.2012.01908.x CrossRefGoogle Scholar
  99. 99.
    Gareau MG, Silva MA, Perdue MH (2008) Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med 8(4):274–281CrossRefPubMedCentralGoogle Scholar
  100. 100.
    Baumler AJ, Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535(7610):85–93.  https://doi.org/10.1038/nature18849 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Grishin A, Bowling J, Bell B, Wang J, Ford HR (2016) Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 51(1):13–17.  https://doi.org/10.1016/j.jpedsurg.2015.10.006 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Dopkins N, Nagarkatti PS, Nagarkatti M (2018) The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. Immunology 154(2):178–185.  https://doi.org/10.1111/imm.12903 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Weber MD, Frank MG, Tracey KJ, Watkins LR, Maier SF (2015) Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J Neurosci 35(1):316–324.  https://doi.org/10.1523/JNEUROSCI.3561-14.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Hanamsagar R, Hanke ML, Kielian T (2012) Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol 33(7):333–342.  https://doi.org/10.1016/j.it.2012.03.001 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, Banasr M, Duric V et al (2016) Psychological stress activates the Inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry 80(1):12–22.  https://doi.org/10.1016/j.biopsych.2015.11.026 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Ziemssen T, Kern S (2007) Psychoneuroimmunology--cross-talk between the immune and nervous systems. J Neurol 254(Suppl 2):II8–I11.  https://doi.org/10.1007/s00415-007-2003-8 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 29(2):201–217.  https://doi.org/10.1016/j.pnpbp.2004.11.003 CrossRefGoogle Scholar
  108. 108.
    Abbasi SH, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S (2012) Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord 141(2–3):308–314.  https://doi.org/10.1016/j.jad.2012.03.033 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36(12):2452–2459.  https://doi.org/10.1038/npp.2011.132 CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G et al (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11(7):680–684.  https://doi.org/10.1038/sj.mp.4001805 CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23(2):87–94.  https://doi.org/10.1002/hup.912 CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Foster JA, Rinaman L, Cryan JF (2017) Stress & the gut-brain axis: regulation by the microbiome. Neurobiol Stress 7:124–136.  https://doi.org/10.1016/j.ynstr.2017.03.001 CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Hayley S, Poulter MO, Merali Z, Anisman H (2005) The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135(3):659–678.  https://doi.org/10.1016/j.neuroscience.2005.03.051 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Kim YK, Jung HG, Myint AM, Kim H, Park SH (2007) Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 104(1–3):91–95.  https://doi.org/10.1016/j.jad.2007.02.018 CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Licinio J, Frost P (2000) The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics. Braz J Med Biol Res 33(10):1141–1148CrossRefPubMedCentralGoogle Scholar
  116. 116.
    Licinio J, Wong ML (1999) The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4(4):317–327CrossRefPubMedCentralGoogle Scholar
  117. 117.
    Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, van Beveren N, Cohen D, Versnel MA, Nolen WA, Drexhage HA (2010) Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients. Int J Neuropsychopharmacol 13(10):1369–1381.  https://doi.org/10.1017/S1461145710000799 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Prolo P, Licinio J (1999) Cytokines in affective disorders and schizophrenia: new clinical and genetic findings. Mol Psychiatry 4(4):396CrossRefPubMedCentralGoogle Scholar
  119. 119.
    Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E (2007) Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry 7:46.  https://doi.org/10.1186/1471-244X-7-46 CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Rausch JL (2005) Initial conditions of psychotropic drug response: studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome. Prog Neuro-Psychopharmacol Biol Psychiatry 29(6):1046–1061.  https://doi.org/10.1016/j.pnpbp.2005.03.011 CrossRefGoogle Scholar
  121. 121.
    Tourjman V, Kouassi E, Koue ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, Potvin S (2013) Antipsychotics’ effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res 151(1–3):43–47.  https://doi.org/10.1016/j.schres.2013.10.011 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Raison CL, Miller AH (2013) Do cytokines really sing the blues? Cerebrum 2013:10PubMedPubMedCentralGoogle Scholar
  123. 123.
    Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Annu Rev Immunol 28:321–342.  https://doi.org/10.1146/annurev-immunol-030409-101311 CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Fleshner M (2013) Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome. Brain Behav Immun 27(1):1–7.  https://doi.org/10.1016/j.bbi.2012.08.012 CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Gadek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J (2013) Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol Rep 65(6):1655–1662CrossRefPubMedCentralGoogle Scholar
  126. 126.
    Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry 19(1):11–38CrossRefGoogle Scholar
  127. 127.
    Maes M (1993) A review on the acute phase response in major depression. Rev Neurosci 4(4):407–416CrossRefPubMedCentralGoogle Scholar
  128. 128.
    Kling MA, Alesci S, Csako G, Costello R, Luckenbaugh DA, Bonne O, Duncko R, Drevets WC et al (2007) Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biol Psychiatry 62(4):309–313.  https://doi.org/10.1016/j.biopsych.2006.09.033 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Gardner A, Boles RG (2011) Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):730–743.  https://doi.org/10.1016/j.pnpbp.2010.07.030 CrossRefGoogle Scholar
  130. 130.
    Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35(4):298–306CrossRefPubMedCentralGoogle Scholar
  131. 131.
    Capuron L, Schroecksnadel S, Feart C, Aubert A, Higueret D, Barberger-Gateau P, Laye S, Fuchs D (2011) Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry 70(2):175–182.  https://doi.org/10.1016/j.biopsych.2010.12.006 CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Dieperink E, Willenbring M, Ho SB (2000) Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 157(6):867–876CrossRefPubMedCentralGoogle Scholar
  133. 133.
    Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21(2):153–160.  https://doi.org/10.1016/j.bbi.2006.09.006 CrossRefGoogle Scholar
  134. 134.
    Vergassola C, Pende A, Musso NR, Ioverno A, Lotti G, Criscuolo D (1990) Effects of interferon alpha-2a on catecholamines and lymphocyte beta 2 adrenoceptors in healthy humans. Int J Neurosci 51(3–4):211–213CrossRefPubMedCentralGoogle Scholar
  135. 135.
    Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller AH (2012) Molecular signatures of peripheral blood mononuclear cells during chronic interferon-alpha treatment: relationship with depression and fatigue. Psychol Med 42(8):1591–1603.  https://doi.org/10.1017/S0033291711002868 CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Konsman JP, Parnet P, Dantzer R (2002) Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci 25(3):154–159CrossRefPubMedCentralGoogle Scholar
  137. 137.
    Leonard BE (2014) Impact of inflammation on neurotransmitter changes in major depression: an insight into the action of antidepressants. Prog Neuro-Psychopharmacol Biol Psychiatry 48:261–267.  https://doi.org/10.1016/j.pnpbp.2013.10.018 CrossRefGoogle Scholar
  138. 138.
    Rawdin BJ, Mellon SH, Dhabhar FS, Epel ES, Puterman E, Su Y, Burke HM, Reus VI et al (2013) Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun 31:143–152.  https://doi.org/10.1016/j.bbi.2012.11.011 CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67(5):446–457.  https://doi.org/10.1016/j.biopsych.2009.09.033 CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27(1):24–31.  https://doi.org/10.1016/j.it.2005.11.006 CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Maes M, Song C, Lin A, De Jongh R, Van Gastel A, Kenis G, Bosmans E, De Meester I et al (1998) The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10(4):313–318CrossRefGoogle Scholar
  142. 142.
    Myint AM, Leonard BE, Steinbusch HW, Kim YK (2005) Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 88(2):167–173.  https://doi.org/10.1016/j.jad.2005.07.008 CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Song C, Halbreich U, Han C, Leonard BE, Luo H (2009) Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 42(5):182–188.  https://doi.org/10.1055/s-0029-1202263 CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Huang TL, Lee CT (2007) T-helper 1/T-helper 2 cytokine imbalance and clinical phenotypes of acute-phase major depression. Psychiatry Clin Neurosci 61(4):415–420.  https://doi.org/10.1111/j.1440-1819.2007.01686.x CrossRefGoogle Scholar
  145. 145.
    Mahar I, Bambico FR, Mechawar N, Nobrega JN (2014) Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev 38:173–192.  https://doi.org/10.1016/j.neubiorev.2013.11.009 CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, Wang W, Tang W et al (2015) Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 48:186–194.  https://doi.org/10.1016/j.bbi.2015.03.016 CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157(1):115–118.  https://doi.org/10.1176/ajp.157.1.115 CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Pannekoek JN, van der Werff SJ, van den Bulk BG, van Lang ND, Rombouts SA, van Buchem MA, Vermeiren RR, van der Wee NJ (2014) Reduced anterior cingulate gray matter volume in treatment-naive clinically depressed adolescents. Neuroimage Clin 4:336–342.  https://doi.org/10.1016/j.nicl.2014.01.007 CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Lee BH, Kim YK (2010) The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 7(4):231–235.  https://doi.org/10.4306/pi.2010.7.4.231 CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 98(22):12796–12801.  https://doi.org/10.1073/pnas.211427898 CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Dwivedi Y (2009) Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat 5:433–449CrossRefPubMedCentralGoogle Scholar
  152. 152.
    Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio A, Bianchi C, Mannari C, Martini C et al (2008) Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J Affect Disord 105(1–3):279–283.  https://doi.org/10.1016/j.jad.2007.05.005 CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Mohle L, Mattei D, Heimesaat MM, Bereswill S, Fischer A, Alutis M, French T, Hambardzumyan D et al (2016) Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep 15(9):1945–1956.  https://doi.org/10.1016/j.celrep.2016.04.074 CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O'Leary OF (2015) Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry 78(4):e7–e9.  https://doi.org/10.1016/j.biopsych.2014.12.023 CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):676–692.  https://doi.org/10.1016/j.pnpbp.2010.05.004 CrossRefGoogle Scholar
  156. 156.
    Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74.  https://doi.org/10.2174/157015909787602823 CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW (2015) Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 51:164–175.  https://doi.org/10.1016/j.psyneuen.2014.09.025 CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R (2003) Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep 8(6):365–370.  https://doi.org/10.1179/135100003225003393 CrossRefGoogle Scholar
  159. 159.
    Yager S, Forlenza MJ, Miller GE (2010) Depression and oxidative damage to lipids. Psychoneuroendocrinology 35(9):1356–1362.  https://doi.org/10.1016/j.psyneuen.2010.03.010 CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S (2007) Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol 22(2):67–73.  https://doi.org/10.1002/hup.829 CrossRefGoogle Scholar
  161. 161.
    Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2′-deoxyguanosine in clinical depression. Psychosom Med 68(1):1–7.  https://doi.org/10.1097/01.psy.0000195780.37277.2a CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. Neuro Endocrinol Lett 28(6):861–867PubMedPubMedCentralGoogle Scholar
  163. 163.
    Maes M, Mihaylova I, Kubera M, Leunis JC (2008) An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS. Neuro Endocrinol Lett 29(3):313–319PubMedPubMedCentralGoogle Scholar
  164. 164.
    Kotan VO, Sarandol E, Kirhan E, Ozkaya G, Kirli S (2011) Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up study. Prog Neuro-Psychopharmacol Biol Psychiatry 35(5):1284–1290.  https://doi.org/10.1016/j.pnpbp.2011.03.021 CrossRefGoogle Scholar
  165. 165.
    Tsuboi H, Shimoi K, Kinae N, Oguni I, Hori R, Kobayashi F (2004) Depressive symptoms are independently correlated with lipid peroxidation in a female population: comparison with vitamins and carotenoids. J Psychosom Res 56(1):53–58.  https://doi.org/10.1016/S0022-3999(03)00567-1 CrossRefGoogle Scholar
  166. 166.
    Zafir A, Banu N (2007) Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats. Eur J Pharmacol 572(1):23–31.  https://doi.org/10.1016/j.ejphar.2007.05.062 CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Gibson SA, Korade Z, Shelton RC (2012) Oxidative stress and glutathione response in tissue cultures from persons with major depression. J Psychiatr Res 46(10):1326–1332.  https://doi.org/10.1016/j.jpsychires.2012.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Scapagnini G, Davinelli S, Drago F, De Lorenzo A, Oriani G (2012) Antioxidants as antidepressants: fact or fiction? CNS Drugs 26(6):477–490.  https://doi.org/10.2165/11633190-000000000-00000 CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Harkin A, Connor TJ, Burns MP, Kelly JP (2004) Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur Neuropsychopharmacol 14(4):274–281.  https://doi.org/10.1016/j.euroneuro.2003.08.010 CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Joca SR, Guimaraes FS (2006) Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 185(3):298–305.  https://doi.org/10.1007/s00213-006-0326-2 CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Lee BH, Lee SW, Yoon D, Lee HJ, Yang JC, Shim SH, Kim DH, Ryu SH et al (2006) Increased plasma nitric oxide metabolites in suicide attempters. Neuropsychobiology 53(3):127–132.  https://doi.org/10.1159/000092542 CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Gandhi S, Abramov AY (2012) Mechanism of oxidative stress in neurodegeneration. Oxidative Med Cell Longev 2012:428010.  https://doi.org/10.1155/2012/428010 CrossRefGoogle Scholar
  173. 173.
    Pan Y, Chen XY, Zhang QY, Kong LD (2014) Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun 41:90–100.  https://doi.org/10.1016/j.bbi.2014.04.007 CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Zhang Y, Liu L, Peng YL, Liu YZ, Wu TY, Shen XL, Zhou JR, Sun DY et al (2014) Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci Ther 20(2):119–124.  https://doi.org/10.1111/cns.12170 CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Zhang Y, Liu L, Liu YZ, Shen XL, Wu TY, Zhang T, Wang W, Wang YX et al (2015) NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int J Neuropsychopharmacol 18(8).  https://doi.org/10.1093/ijnp/pyv006 CrossRefPubMedCentralGoogle Scholar
  176. 176.
    Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13(7):717–728.  https://doi.org/10.1038/sj.mp.4002055 CrossRefGoogle Scholar
  177. 177.
    Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 105(2):751–756.  https://doi.org/10.1073/pnas.0708092105 CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Too LK, Mitchell AJ, Yau B, Ball HJ, McGregor IS, Hunt NH (2014) Interleukin-18 deficiency and its long-term behavioural and cognitive impacts in a murine model of pneumococcal meningitis. Behav Brain Res 263:176–189.  https://doi.org/10.1016/j.bbr.2014.01.035 CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Sugama S, Wirz SA, Barr AM, Conti B, Bartfai T, Shibasaki T (2004) Interleukin-18 null mice show diminished microglial activation and reduced dopaminergic neuron loss following acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. Neuroscience 128(2):451–458.  https://doi.org/10.1016/j.neuroscience.2004.07.020 CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Sugama S, Fujita M, Hashimoto M, Conti B (2007) Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18. Neuroscience 146(3):1388–1399.  https://doi.org/10.1016/j.neuroscience.2007.02.043 CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:315.  https://doi.org/10.3389/fnins.2014.00315 CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837.  https://doi.org/10.1038/nri2873 CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Schaefer L (2014) Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem 289(51):35237–35245.  https://doi.org/10.1074/jbc.R114.619304 CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Fleshner M, Campisi J, Amiri L, Diamond DM (2004) Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 29(9):1142–1152.  https://doi.org/10.1016/j.psyneuen.2004.01.007 CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Creagh EM, O'Neill LA (2006) TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27(8):352–357.  https://doi.org/10.1016/j.it.2006.06.003 CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW (2014) Pattern recognition receptors and central nervous system repair. Exp Neurol 258:5–16.  https://doi.org/10.1016/j.expneurol.2014.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Ganter MT, Ware LB, Howard M, Roux J, Gartland B, Matthay MA, Fleshner M, Pittet JF (2006) Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am J Physiol Lung Cell Mol Physiol 291(3):L354–L361.  https://doi.org/10.1152/ajplung.00405.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Slavich GM, Cole SW (2013) The emerging field of human social genomics. Clin Psychol Sci 1(3):331–348CrossRefPubMedCentralGoogle Scholar
  189. 189.
    Dantzer R (2009) Cytokine, sickness behavior, and depression. Immunol Allergy Clin N Am 29(2):247–264.  https://doi.org/10.1016/j.iac.2009.02.002 CrossRefGoogle Scholar
  190. 190.
    Guo H, Callaway JB, Ting JP (2015) Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat Med 21(7):677–687.  https://doi.org/10.1038/nm.3893 CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117(5):561–574.  https://doi.org/10.1016/j.cell.2004.05.004 CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550.  https://doi.org/10.1146/annurev.immunol.021908.132612 CrossRefGoogle Scholar
  193. 193.
    Menu P, Vince JE (2011) The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol 166(1):1–15.  https://doi.org/10.1111/j.1365-2249.2011.04440.x CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Lawson MA, McCusker RH, Kelley KW (2013) Interleukin-1 beta converting enzyme is necessary for development of depression-like behavior following intracerebroventricular administration of lipopolysaccharide to mice. J Neuroinflammation 10:54.  https://doi.org/10.1186/1742-2094-10-54 CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Mastronardi C, Whelan F, Yildiz OA, Hannestad J, Elashoff D, McCann SM, Licinio J, Wong ML (2007) Caspase 1 deficiency reduces inflammation-induced brain transcription. Proc Natl Acad Sci U S A 104(17):7205–7210.  https://doi.org/10.1073/pnas.0701366104 CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Mastronardi CA, Paz-Filho G, Zanoni M, Molano-Gonzalez N, Arcos-Burgos M, Licinio J, Wong ML (2015) Temporal gene expression in the hippocampus and peripheral organs to endotoxin-induced systemic inflammatory response in caspase-1-deficient mice. Neuroimmunomodulation 22(4):263–273.  https://doi.org/10.1159/000368310 CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, McDowell J, Paskind M et al (1995) Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 80(3):401–411CrossRefPubMedCentralGoogle Scholar
  198. 198.
    Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20(2):145–155.  https://doi.org/10.1038/nn.4476 CrossRefGoogle Scholar
  199. 199.
    Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci Signal 3(105):cm1.  https://doi.org/10.1126/scisignal.3105cm1 CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Kim YK, Paik JW, Lee SW, Yoon D, Han C, Lee BH (2006) Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog Neuro-Psychopharmacol Biol Psychiatry 30(6):1091–1096.  https://doi.org/10.1016/j.pnpbp.2006.04.008 CrossRefGoogle Scholar
  201. 201.
    Suzuki E, Yagi G, Nakaki T, Kanba S, Asai M (2001) Elevated plasma nitrate levels in depressive states. J Affect Disord 63(1–3):221–224CrossRefPubMedCentralGoogle Scholar
  202. 202.
    Galecki P, Galecka E, Maes M, Chamielec M, Orzechowska A, Bobinska K, Lewinski A, Szemraj J (2012) The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. J Affect Disord 138(3):360–366.  https://doi.org/10.1016/j.jad.2012.01.016 CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Galecki P, Maes M, Florkowski A, Lewinski A, Galecka E, Bienkiewicz M, Szemraj J (2010) An inducible nitric oxide synthase polymorphism is associated with the risk of recurrent depressive disorder. Neurosci Lett 486(3):184–187.  https://doi.org/10.1016/j.neulet.2010.09.048 CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Maes M, Kubera M, Mihaylova I, Geffard M, Galecki P, Leunis JC, Berk M (2013) Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression. J Affect Disord 149(1–3):23–29.  https://doi.org/10.1016/j.jad.2012.06.039 CrossRefGoogle Scholar
  205. 205.
    Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M (2011) IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord 135(1–3):414–418.  https://doi.org/10.1016/j.jad.2011.08.023 CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Finkel MS, Laghrissi-Thode F, Pollock BG, Rong J (1996) Paroxetine is a novel nitric oxide synthase inhibitor. Psychopharmacol Bull 32(4):653–658PubMedPubMedCentralGoogle Scholar
  207. 207.
    Di Paolo NC, Shayakhmetov DM (2016) Interleukin 1alpha and the inflammatory process. Nat Immunol 17(8):906–913.  https://doi.org/10.1038/ni.3503 CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, Azam T, Kim S et al (2013) The interleukin-1alpha precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines. Front Immunol 4:391.  https://doi.org/10.3389/fimmu.2013.00391 CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Kurt-Jones EA, Beller DI, Mizel SB, Unanue ER (1985) Identification of a membrane-associated interleukin 1 in macrophages. Proc Natl Acad Sci U S A 82(4):1204–1208CrossRefPubMedCentralGoogle Scholar
  210. 210.
    Bersudsky M, Luski L, Fishman D, White RM, Ziv-Sokolovskaya N, Dotan S, Rider P, Kaplanov I et al (2014) Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice. Gut 63(4):598–609.  https://doi.org/10.1136/gutjnl-2012-303329 CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Wang X, Wu H, Miller AH (2004) Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry 9(1):65–75.  https://doi.org/10.1038/sj.mp.4001339 CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Arend WP, Palmer G, Gabay C (2008) IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 223:20–38.  https://doi.org/10.1111/j.1600-065X.2008.00624.x CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Sugama S, Conti B (2008) Interleukin-18 and stress. Brain Res Rev 58(1):85–95.  https://doi.org/10.1016/j.brainresrev.2007.11.003 CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA (2004) Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci U S A 101(23):8815–8820.  https://doi.org/10.1073/pnas.0402800101 CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Smith DE (2011) The biological paths of IL-1 family members IL-18 and IL-33. J Leukoc Biol 89(3):383–392.  https://doi.org/10.1189/jlb.0810470 CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K et al (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8(3):383–390CrossRefGoogle Scholar
  217. 217.
    Yamamoto Y, Tanahashi T, Katsuura S, Kurokawa K, Nishida K, Kuwano Y, Kawai T, Teshima-Kondo S et al (2010) Interleukin-18 deficiency reduces neuropeptide gene expressions in the mouse amygdala related with behavioral change. J Neuroimmunol 229(1–2):129–139.  https://doi.org/10.1016/j.jneuroim.2010.07.024 CrossRefPubMedPubMedCentralGoogle Scholar
  218. 218.
    Sekiyama A, Ueda H, Kashiwamura S, Sekiyama R, Takeda M, Rokutan K, Okamura H (2005) A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation. Immunity 22(6):669–677.  https://doi.org/10.1016/j.immuni.2005.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Montezuma K, Biojone C, Lisboa SF, Cunha FQ, Guimaraes FS, Joca SR (2012) Inhibition of iNOS induces antidepressant-like effects in mice: Pharmacological and genetic evidence. Neuropharmacology 62(1):485–491.  https://doi.org/10.1016/j.neuropharm.2011.09.004 CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Dhir A, Kulkarni SK (2007) Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor. Eur J Pharmacol 568(1–3):177–185.  https://doi.org/10.1016/j.ejphar.2007.04.028 CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490.  https://doi.org/10.1016/j.immuni.2005.09.015 CrossRefGoogle Scholar
  222. 222.
    Haraldsen G, Balogh J, Pollheimer J, Sponheim J, Kuchler AM (2009) Interleukin-33 - cytokine of dual function or novel alarmin? Trends Immunol 30(5):227–233.  https://doi.org/10.1016/j.it.2009.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Maywald RL, Doerner SK, Pastorelli L, De Salvo C, Benton SM, Dawson EP, Lanza DG, Berger NA et al (2015) IL-33 activates tumor stroma to promote intestinal polyposis. Proc Natl Acad Sci U S A 112(19):E2487–E2496.  https://doi.org/10.1073/pnas.1422445112 CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Esplugues JV (2002) NO as a signalling molecule in the nervous system. Br J Pharmacol 135(5):1079–1095.  https://doi.org/10.1038/sj.bjp.0704569 CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Ankarali S, Ankarali HC, Marangoz C (2009) Further evidence for the role of nitric oxide in maternal aggression: effects of L-NAME on maternal aggression towards female intruders in Wistar rats. Physiol Res 58(4):591–598PubMedPubMedCentralGoogle Scholar
  226. 226.
    Liu RP, Zou M, Wang JY, Zhu JJ, Lai JM, Zhou LL, Chen SF, Zhang X et al (2014) Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J Neuroinflammation 11:47.  https://doi.org/10.1186/1742-2094-11-47 CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Yun HY, Dawson VL, Dawson TM (1997) Nitric oxide in health and disease of the nervous system. Mol Psychiatry 2(4):300–310CrossRefPubMedCentralGoogle Scholar
  228. 228.
    Wong ML, Rettori V, al-Shekhlee A, Bongiorno PB, Canteros G, McCann SM, Gold PW, Licinio J (1996) Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nat Med 2(5):581–584CrossRefPubMedCentralGoogle Scholar
  229. 229.
    Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, Nelson BJ, Nacy CA (1994) Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. Immunol Lett 43(1–2):87–94CrossRefPubMedCentralGoogle Scholar
  230. 230.
    Musial A, Eissa NT (2001) Inducible nitric-oxide synthase is regulated by the proteasome degradation pathway. J Biol Chem 276(26):24268–24273.  https://doi.org/10.1074/jbc.M100725200 CrossRefPubMedPubMedCentralGoogle Scholar
  231. 231.
    Karolewicz B, Paul IA, Antkiewicz-Michaluk L (2001) Effect of NOS inhibitor on forced swim test and neurotransmitters turnover in the mouse brain. Pol J Pharmacol 53(6):587–596PubMedPubMedCentralGoogle Scholar
  232. 232.
    Moncada S, Higgs EA (1995) Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J 9(13):1319–1330CrossRefPubMedCentralGoogle Scholar
  233. 233.
    Ikenouchi-Sugita A, Yoshimura R, Hori H, Umene-Nakano W, Ueda N, Nakamura J (2009) Effects of antidepressants on plasma metabolites of nitric oxide in major depressive disorder: comparison between milnacipran and paroxetine. Prog Neuro-Psychopharmacol Biol Psychiatry 33(8):1451–1453.  https://doi.org/10.1016/j.pnpbp.2009.07.028 CrossRefGoogle Scholar
  234. 234.
    Sandor NT, Brassai A, Puskas A, Lendvai B (1995) Role of nitric oxide in modulating neurotransmitter release from rat striatum. Brain Res Bull 36(5):483–486CrossRefPubMedCentralGoogle Scholar
  235. 235.
    Dhir A, Kulkarni SK (2011) Nitric oxide and major depression. Nitric Oxide 24(3):125–131.  https://doi.org/10.1016/j.niox.2011.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Rivera-Chavez F, Zhang LF, Faber F, Lopez CA, Byndloss MX, Olsan EE, Xu G, Velazquez EM et al (2016) Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of salmonella. Cell Host Microbe 19(4):443–454.  https://doi.org/10.1016/j.chom.2016.03.004 CrossRefPubMedPubMedCentralGoogle Scholar
  237. 237.
    Byndloss MX, Olsan EE, Rivera-Chavez F, Tiffany CR, Cevallos SA, Lokken KL, Torres TP, Byndloss AJ et al (2017) Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357(6351):570–575.  https://doi.org/10.1126/science.aam9949 CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Klena J, Zhang P, Schwartz O, Hull S, Chen T (2005) The core lipopolysaccharide of Escherichia coli is a ligand for the dendritic-cell-specific intercellular adhesion molecule nonintegrin CD209 receptor. J Bacteriol 187(5):1710–1715.  https://doi.org/10.1128/JB.187.5.1710-1715.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Tse JKY (2017) Gut microbiota, nitric oxide, and microglia as prerequisites for neurodegenerative disorders. ACS Chem Neurosci 8(7):1438–1447.  https://doi.org/10.1021/acschemneuro.7b00176 CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189.  https://doi.org/10.1189/jlb.0603252 CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Meyer O (2009) Interferons and autoimmune disorders. Joint Bone Spine 76(5):464–473.  https://doi.org/10.1016/j.jbspin.2009.03.012 CrossRefPubMedPubMedCentralGoogle Scholar
  242. 242.
    Subramaniam PS, Torres BA, Johnson HM (2001) So many ligands, so few transcription factors: a new paradigm for signaling through the STAT transcription factors. Cytokine 15(4):175–187.  https://doi.org/10.1006/cyto.2001.0905 CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Ramana CV, Gil MP, Schreiber RD, Stark GR (2002) Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23(2):96–101CrossRefPubMedCentralGoogle Scholar
  244. 244.
    Kim TK, Maniatis T (1996) Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science 273(5282):1717–1719CrossRefPubMedCentralGoogle Scholar
  245. 245.
    Boehm U, Klamp T, Groot M, Howard JC (1997) Cellular responses to interferon-gamma. Annu Rev Immunol 15:749–795.  https://doi.org/10.1146/annurev.immunol.15.1.749 CrossRefPubMedPubMedCentralGoogle Scholar
  246. 246.
    Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513–545.  https://doi.org/10.1146/annurev-immunol-032713-120231 CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ (2009) INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res 37(Database issue):D852–D857.  https://doi.org/10.1093/nar/gkn732 CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K et al (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275(5297):206–209CrossRefPubMedCentralGoogle Scholar
  249. 249.
    Hu X, Ivashkiv LB (2009) Cross-regulation of signaling pathways by interferon-gamma: Implications for immune responses and autoimmune diseases. Immunity 31(4):539–550.  https://doi.org/10.1016/j.immuni.2009.09.002 CrossRefPubMedPubMedCentralGoogle Scholar
  250. 250.
    Hu X, Chen J, Wang L, Ivashkiv LB (2007) Crosstalk among Jak-STAT, toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol 82(2):237–243.  https://doi.org/10.1189/jlb.1206763 CrossRefPubMedPubMedCentralGoogle Scholar
  251. 251.
    Dai C, Krantz SB (1999) Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood 93(10):3309–3316PubMedPubMedCentralGoogle Scholar
  252. 252.
    Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D'Hondt P, Vanden Bossche BV, Cosyns P (1994) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 54(2):143–160CrossRefPubMedCentralGoogle Scholar
  253. 253.
    Kahl KG, Kruse N, Faller H, Weiss H, Rieckmann P (2002) Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis. Psychoneuroendocrinology 27(6):671–681CrossRefPubMedCentralGoogle Scholar
  254. 254.
    Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP (2001) Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol 58(7):1081–1086CrossRefPubMedCentralGoogle Scholar
  255. 255.
    Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R, Bosmans E, Scharpe S (1999) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20(4):370–379.  https://doi.org/10.1016/S0893-133X(98)00088-8 CrossRefPubMedPubMedCentralGoogle Scholar
  256. 256.
    Myint AM, Bondy B, Baghai TC, Eser D, Nothdurfter C, Schule C, Zill P, Muller N et al (2013) Tryptophan metabolism and immunogenetics in major depression: a role for interferon-gamma gene. Brain Behav Immun 31:128–133.  https://doi.org/10.1016/j.bbi.2013.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    Raitala A, Pertovaara M, Karjalainen J, Oja SS, Hurme M (2005) Association of interferon-gamma +874(T/a) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol 61(4):387–390.  https://doi.org/10.1111/j.1365-3083.2005.01586.x CrossRefPubMedPubMedCentralGoogle Scholar
  258. 258.
    Oxenkrug GF (2011) Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. J Neural Transm (Vienna) 118(1):75–85.  https://doi.org/10.1007/s00702-010-0475-7 CrossRefGoogle Scholar
  259. 259.
    O'Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW et al (2009) Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci 29(13):4200–4209.  https://doi.org/10.1523/JNEUROSCI.5032-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  260. 260.
    Konan KV, Taylor MW (1996) Importance of the two interferon-stimulated response element (ISRE) sequences in the regulation of the human indoleamine 2,3-dioxygenase gene. J Biol Chem 271(32):19140–19145CrossRefPubMedCentralGoogle Scholar
  261. 261.
    O'Garra A, Arai N (2000) The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol 10(12):542–550CrossRefPubMedCentralGoogle Scholar
  262. 262.
    Smeltz RB, Chen J, Ehrhardt R, Shevach EM (2002) Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression. J Immunol 168(12):6165–6172CrossRefPubMedCentralGoogle Scholar
  263. 263.
    Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM et al (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259(5102):1742–1745CrossRefPubMedCentralGoogle Scholar
  264. 264.
    Litteljohn D, Cummings A, Brennan A, Gill A, Chunduri S, Anisman H, Hayley S (2010) Interferon-gamma deficiency modifies the effects of a chronic stressor in mice: implications for psychological pathology. Brain Behav Immun 24(3):462–473.  https://doi.org/10.1016/j.bbi.2009.12.001 CrossRefPubMedPubMedCentralGoogle Scholar
  265. 265.
    Campos AC, Vaz GN, Saito VM, Teixeira AL (2014) Further evidence for the role of interferon-gamma on anxiety- and depressive-like behaviors: involvement of hippocampal neurogenesis and NGF production. Neurosci Lett 578:100–105.  https://doi.org/10.1016/j.neulet.2014.06.039 CrossRefPubMedPubMedCentralGoogle Scholar
  266. 266.
    Kustova Y, Sei Y, Morse HC Jr, Basile AS (1998) The influence of a targeted deletion of the IFNgamma gene on emotional behaviors. Brain Behav Immun 12(4):308–324.  https://doi.org/10.1006/brbi.1998.0546 CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Clark E, Hoare C, Tanianis-Hughes J, Carlson GL, Warhurst G (2005) Interferon gamma induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft-mediated process. Gastroenterology 128(5):1258–1267CrossRefPubMedCentralGoogle Scholar

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© The Author(s) 2018

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Mind and Brain ThemeSouth Australian Health and Medical Research InstituteAdelaideAustralia
  2. 2.Department of Psychiatry, College of Medicine and Public HealthFlinders UniversityBedford ParkAustralia
  3. 3.Centre for NeuroscienceFlinders UniversityBedford ParkAustralia
  4. 4.School of Medicine and Health SciencesUniversidad Del RosarioBogotaColombia
  5. 5.Neuroscience (NEUROS) Research GroupUniversidad del RosarioBogotaColombia
  6. 6.Infection and Immunity ThemeSouth Australia Health and Medical Research InstituteAdelaideAustralia
  7. 7.SAHMRI Microbiome Research LaboratoryFlinders University College of Medicine and Public HealthBedford ParkAustralia
  8. 8.College of MedicineState University of New York Upstate Medical UniversitySyracuseUSA
  9. 9.Department of PsychiatryState University of New York Upstate Medical UniversitySyracuseUSA

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