An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.
The research, published Sept. 18 in the journal Science Immunology, suggests these immune cells may play a role other than protecting against microbial invaders – protecting our mental health.
The results buttress an emerging theory that gamma interferons, a type of immune cell that helps induce and modulate a variety of immune system responses, may also play a role in preventing depression in healthy people.
“We were surprised that normal spinal fluid would be so interesting,” said David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology, professor of immunobiology and senior author of the study.
Previous research has shown that blocking gamma interferons and the T cells they help produce can cause depression-like symptoms in mice. Hafler notes that depression is also a common side effect in patients with MS treated with a different type of interferon.
Using a powerful new technology that allows a detailed examination of individual cells, the researchers show that while the characteristics of T cells in the spinal fluid of healthy people share similarities with those of MS patients, they lack the ability to replicate and cause the damaging inflammatory response seen in autoimmune diseases such as MS.
In essence, the immune system in the brains of all people is poised to make an inflammatory immune system response and may have another function than defending against pathogens, Hafler said.
“These T cells serve another purpose and we speculate that they may help preserve our mental health,” he said.
Hafler said that his lab and colleagues at Yale plan to explore how immune system responses in the central nervous system might affect psychiatric disorders such as depression.
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 [3–7].
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 [8–13].
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 [14–16].
Newer therapeutic strategies involve drugs acting on neuroplasticity-related pathways, gut microbiome modulation, and deep brain stimulation surgery [17–19].
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, 20–25]. 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 . Similarly, transcription of inducible nitric oxide synthase (NOS2) can be activated by IFNG . Lastly, CASP1 is involved in the epigenetic regulation of NOS2 . 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 . However, excess of oxidative products can elicit oxidative stress and cause protein, lipid, and/or DNA damage . Preclinical and clinical studies suggest that chronic stress exposure is associated with increased ROS production [33–40]. One of the free radicals produced during psychological stress is NO, mainly by NOS2 .
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 [44–46]. 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 . 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 .
Such communication occurs via the endocrine and immune systems, the vagus nerve, and the bacterial metabolome [55–57]. 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 .
At the same time, norepinephrine modulates pro-inflammatory cytokines transcription via beta-adrenergic receptor stimulation .
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 [69–73]. 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 .
This exaggerated response can be reversed by early stage (but not later stage) recolonization with Bifidobacterium infantis . 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 .
Not surprisingly, the gut microbiome modulates microglia homeostasis and maturation, while reduced gut microbiome complexity impairs microglia function . 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 . 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 ).
Glucocorticoids have the effect of restoring homeostasis . 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 [84–88].
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 [91–94].
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”) . It was proposed that the leaky gut phenomenon contributes to MDD .
In fact, stress is known to compromise gut epithelial barrier integrity, allowing gut bacteria to access the enteric nervous system and immune cells . Intestinal inflammation is a major contributor to changes in gut microbiome composition and function that are associated with disease (Reviewed in ). 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 [103–105].
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, 139–144]. 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 [147–150]. 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. (Fig.11).
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  (for a database see ). 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 [248–251].
Ex vivo PBMC from MDD patients display increased IFNG and neopterin production upon stimulation, as well as decreased tryptophan bioavailability . 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 .
At the same time, most categories of antidepressants suppress the IFNG/IL10 ratio through suppressing IFNG and stimulating IL10 [254, 255]. These findings (Table (Table5) suggest5) 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, 258–260].
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 .
Similarly, the presence of the high producer T allele +874(T/A) polymorphism (rs2430561) associates with increased IDO1 activity . 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 .
Clinical evidence of IFNG involvement in MDD
|Ex vivo PBMC from MDD patients display increased IFNG production upon stimulation.|||
|Transcriptional levels of IFNG correlate with depressive symptomatology in multiple sclerosis patients.|||
|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.|||
|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.|||
IFNG−/− mice do not show developmental defects but present compromised immune responses and increased susceptibility to infections . With regard to their behavior, IFNG−/− mice display decreased anxiety- and depressive-like behaviors as well as heightened emotionality in several paradigms [264–266]. 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  (Table 6).
Pre-clinical evidence of IFNG involvement in animal models of MDD
|IFNG−/− mice display decreased anxiety- and depressive-like behaviors as well as heightened emotionality.||[264–266]|
|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.|||
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 . Lastly, IFNG levels affect the representation of specific bacterial species while being up- or downregulated by specific commensals .
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 . 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.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505498/
More information: J.L. Pappalardo el al., “Transcriptomic and clonal characterization of T cells in the human central nervous system,” Science Immunology (2020). immunology.sciencemag.org/look … 6/sciimmunol.abb8786