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Activation of T helper 17 cells may contribute to neuroprogression in depression: proposal of an integrative model

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Abstract

The pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) enhanced O&NS and mitochondrial dysfunction; (ii) microglial activation and excitotoxicity; (iii) increased autoimmune responses; (iv) dysregulation of the gut mucosa and microbiota; and (v) disruption of the blood-brain barrier. The clinical and research implications of this model are discussed.

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Cytokines play a critical role in controlling the differentiation of CD4 Th cells into distinct subsets, including IL-17-producing Th17 cells. Unfortunately, the incidence of a number of autoimmune diseases, particularly those in which the IL-23/IL-17 axis has been implicated, has risen in the last several decades, suggesting that environmental factors can promote autoimmunity. Here we review the role of cytokines in Th17 differentiation, particularly the role of IL-23 in promoting the differentiation of a pathogenic subset of Th17 cells that potently induce autoimmune tissue inflammation. Moreover, we highlight emerging data that indicate that environmental factors, including the intestinal microbiota and changes in diet, can alter normal cytokine regulation with potent effects on Th17 differentiation and thus promote autoimmunity, which has strong implications for human disease.
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Cytokines of the IL-17 family are uniquely placed on the border between immune cells and tissue. Although IL-17 was originally found to induce the activation and mobilization of neutrophils to sites of inflammation, its tissue-specific function is not yet fully understood. The best-studied IL-17 family members, IL-17A and IL-17F, are both typically produced by immune cells such as Th17, γδ T cells and innate lymphoid cells group 3. However, the cells that respond to these cytokines are mostly found in inflamed tissue. As seen in psoriatic skin lesions or in joints of rheumatoid arthritis patients, high levels of IL-17 have been detected in the central nervous system (CNS) during inflammatory responses. Here, we provide a general review of the molecular function of IL-17 and its role in the CNS in particular. Of the different inflammatory conditions of the CNS, we found multiple sclerosis (MS) to be the one most associated with the presence of Th17 cells and IL-17. In particular, many studies using the murine model for MS, experimental autoimmune encephalomyelitis, found a clear association of Th17 and IL-17 with disease severity and progression. We summarize the recent advances made in correlating the presence of IL-17 with impaired blood-brain barrier integrity as well as the activation of astrocytes and microglia and the consequences for disease progression. There is also evidence that IL-17 plays a pathogenic role in the post-ischemic phase of stroke as well as its experimental model. We review the limited but promising data on the sources of post-stroke IL-17 production and its effects on CNS-resident target cells. In addition to MS and stroke, there is also evidence linking high levels of IL-17 to depression, as a frequent comorbidity of several inflammatory diseases, as well as to different types of infections of the CNS. The evidence we supply here suggests that inhibiting the function of the IL-17 cytokine family could have a beneficial effect on pathogenic conditions in the CNS.
Article
Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression – mild cognitive impairment – dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.
Article
Recent literature considers duration of illness (DI) and duration of untreated illness (DUI) as important factors influencing outcome in many psychiatric conditions. The aim of the present article is to analyze the relationship between DI and DUI, and pharmacological response in the different psychiatric disorders with particular emphasis on neurodegenerative aspects. An updated review of the current literature was conducted through PubMed in order to compare different studies focused on DI and DUI, and treatment response in major psychoses and in depressive/anxiety disorders. A significant body of evidence shows that a prolonged DI and DUI is associated with brain abnormalities and poor treatment response, particularly in schizophrenia. Nevertheless, an increasing number of studies point toward a similar conclusion in mood and anxiety disorders as well, even though fewer studies have been published in this field. Given the relationship between a longer DI and DUI, and poor treatment response-not only in schizophrenia but also in mood and anxiety disorders-specific intervention programs aimed to reduce the latency to treatment are definitely envisaged.
Article
Major depressive disorder (MDD) is frequently associated with significant cognitive dysfunction. Furthermore, MDD is often co-morbid with obesity and metabolic disorders. The aim of this review is to evaluate the pathophysiological role obesity and co-morbid metabolic disorders may play in cognitive dysfunction associated with MDD. We conducted a PubMed search from December 1st 2013 to May 31st 2014 of all English language publications including the following keywords: cognition, working memory, attention, executive functioning, inflammation, insulin, brain-derived neurotrophic factor, neurotrophins, incretins, glucagon-like peptide-1, adipokines, diabetes, oxidative stress and glucocorticoids, cross- referenced with MDD and obesity, metabolic disorders or metabolic syndrome. Clinical and epidemiological studies indicate that metabolic disturbances may contribute to cognitive dysfunction in MDD. There are several overlapping pathophysiological mechanisms linking obesity and metabolic abnormalities to MDD, including disturbances in the hypothalamic pituitary adrenal axis, abnormalities in BDNF signaling, adipose-derived hormones, insulin signalling, inflammatory cytokines, as well as oxidative and nitrosative stress pathways. Based on current research results, this article presents several putative mechanisms underlying the effects of obesity and metabolic abnormalities on cognitive dysfunction in MDD. Metabolic MDD may represent a depression subtype with unique patho-etiological mechanisms. The diverse shared pathophysiological mechanisms elucidated in this review may provide novel targets for the prevention and/or treatment of cognitive deficits in MDD.
Article
A priority clinical and research agenda in mood and anxiety disorders is to identify determinants that influence illness trajectory and outcome. Over the past decade, studies have demonstrated a bidirectional relationship between the gut microbiome and brain function (i.e., the micribiota-gut-brain axis). Probiotic treatments and developmental analysis of the microbiome may provide potential treatments and preventative measures for depressive and anxiety disorders. This systematic literature review aims to identify original studies linking the gut microbiota to major depressive disorder and anxiety disorders. Furthermore, this review also searched for original reports focusing on possible therapeutic and preventative effects of probiotics for these debilitating conditions. Accumulating data indicate that the gut microbiota communicates with the CNS through neural, endocrine and immune pathways. Studies in germ-free animals indicate that the microbiota is involved in the regulation of the stress response (e.g., hypothalamic-pituritary-adrenal axis) and in CNS development at critical stages. Probiotics attenuate anxiety and depressive-like behaviors in experimental animal models. Notwithstanding some inconsistencies and methodological limitations across trials, clinical studies suggest that probiotics may mitigate anxiety symptoms. However, future studies should investigate the anxiolytic and antidepressant effects of probiotics in more phenotypically homogeneous populations. In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders.
Article
Objective: Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data. Data sources: We searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method. Study selection: We scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected. Data extraction: We included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score. Results: In our case-control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] μmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, -0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049). Conclusions: This meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients.
Article
Background Comorbid psychiatric disorders, cardiovascular disease, chronic hypertension, diabetes, and musculoskeletal disorders are highly prevalent in depression. However, the extent to which these conditions affect the recurrence of depression-related work disability is unknown. The specific aims of the study were to investigate the extent to which comorbid other psychiatric disorders, cardiometabolic, and musculoskeletal conditions were associated with the recurrence of depression-related work disability among employees who had returned to work after a depression-related disability episode. MethodsA cohort study of Finnish public sector employees with at least one depression-related disability episode during 2005-2011 after which the employee had returned to work (14,172 depression-related work disability episodes derived from national health and disability registers for 9,946 individuals). We used Cox proportional hazard models for recurrent events. ResultsDepression-related work disability recurred in 35% of the episodes that had ended in return to work from a previous episode, totaling 4,927 recurrent episodes among 3,095 (31%) employees. After adjustment for sex, age, socioeconomic status, and type of employment contract, comorbid psychiatric disorder (hazard ratio = 1.82, 95% CI 1.68-1.97), cardiovascular disease (1.39, 95% CI 1.04-1.87), diabetes (1.43, 95% CI 1.11-1.85), chronic hypertension (1.33, 95% CI 1.11-1.58), and musculoskeletal disorder (1.17, 95% CI 1.06-1.28) were associated with an increased risk of a recurrent episode compared to those without these comorbid conditions. Conclusions Recurrence of depression-related work disability is common. Employees with comorbid psychiatric, cardiometabolic, or musculoskeletal conditions are at an increased risk of recurrent depression-related work disability episodes. (C) 2014 Wiley Periodicals, Inc.
Introduction: Allergic rhinitis (AR) is an IgE-mediated non-infectious disease of the nasal mucosa following contact with allergens. Objective: To investigate the peripheral Th17 cells and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and the expression of cytokines in the serum of AR patients. Methods: The peripheral blood of 14 patients with AR (AR group) and six healthy subjects (control group) was collected from March to May of 2012. Flow cytometry was performed to detect the Th17 cells and Treg cells, and enzyme-linked immunosorbent assay (ELISA) to measure the serum levels of IL-17 and TGF-β1. Results: The proportion of Th17 cells in the AR group was markedly higher than that in the control group (p < 0.01). The proportion of Treg cells in the AR group was also dramatically reduced when compared with the control group (p < 0.01). In the AR group, serum IL-17 levels were markedly higher than those in the control group (p < 0.01). In the AR group, serum TGF-β1 levels were significantly lower than those in the control group (p < 0.01). Conclusion: The imbalance of peripheral Th17/Treg cells plays an important role in the pathogenesis of AR.
Article
Within the NOD-like receptor (NLR) family there are several NLRP (NLR family, Pyrin domain containing) proteins that are involved in the formation of inflammasomes. These multi-protein complexes are a key part of the network of cellular events required for secretion of the pro-inflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome is the best-characterized member of the family and has recently been implicated in gut homeostasis and determining the severity of inflammation in inflammatory bowel disease (IBD) and inflammation-associated colorectal cancer. This led to the discovery that NLRP6 and NLRP12 also contribute to the maintenance of intestinal homeostasis and modulation of the gut microbiota, which in turn influences the intestine and distant organs. In this review we bring together the latest data on the potential roles of NLRP family members in gut health and disease and identify the most pressing questions that remain to be answered to further our understanding of human diseases including IBD, inflammation-associated cancers and metabolic syndromes linked with obesity.
Article
Multiple sclerosis (MS) is the most important autoimmune disease of the central nervous system (CNS). Its animal model experimental autoimmune encephalomyelitis (EAE) has been instrumental in defining the features of the novel T helper cell subset Th17. Conversely, the broad characterization of Th17 immune responses has substantially advanced our understanding of organ-specific autoimmunity and inspired almost a decade of immunological research. Here, we review the current knowledge on Th17 cells and their contribution to the immunopathology in EAE and MS, covering recent proceedings in the induction, modulation and effector mechanisms of this versatile T lymphocyte subset. In particular, we discuss the emerging role of mucosal immunity in the regulation of Th17 cells and CNS autoimmunity, the accumulating evidence for extensive plasticity in the Th17 subset, and their molecular mode of action in promoting this debilitating disease.
Article
Depression has been conceptualized as a disorder driven by immuno-inflammatory pathways and oxidative and nitrosative stress. These factors couple to the induction of neuroregulatory tryptophan catabolites via the activation of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Oxidative damage to neoepitopes increases autoimmune responses, changing the nature of the neural substrate of recurrent depression, which leads to neuroprogression and drives treatment resistance. A number of pro-inflammatory cytokines are linked to these processes. Here, we focus on the role of interleukin (IL)-6 in depression and its associated disorders; we highlight the progress made since the first paper showing increased IL-6 levels was published 20 years ago by Maes and colleagues. When coupled with increased levels of the soluble IL-6 receptor in depression, higher levels of IL-6 may indicate increased IL-6 trans-signaling, whereby IL-6 receptor signaling occurs in cells not normally expressing the IL-6 receptor. It has been suggested that IL-6 is intimately associated with two crucial aspects of depression, as well as central inflammation more broadly. First, the regulation of the local inflammatory response via its interactions with macrophage and glia melatonin production is coupled to local epigenetic modulation via methyl CpG-binding protein 2 (MeCP2). Second, the more systemic regulation of tryptophan availability occurs via the IL-6 induction of IDO. Coupled to its role in the regulation of autoimmune associated T-helper 17 cells and IL-17 production, IL-6 has wide and differential impacts on processes driving depression and a wider range of psychiatric and neurodegenerative conditions.
Article
The present study was to examine the role of pro-inflammatory T helper 17 (Th17) cells in drug naïve, first episode schizophrenia. Patients with normal weight, drug naïve, first episode schizophrenia and healthy controls were enrolled in the study. Flow cytometric analysis was performed to analyze the proportion of Th17 cells among the CD4+ T cells. Plasma levels of interleukin-17 (IL-17), interferon-γ (IFN-γ) and interleukin-6 (IL-6) were examined using enzyme-linked immunosorbent assay (ELISA). Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). All measures were repeated for the patient group after 4 weeks of risperidone treatment. Sixty-nine patients with normal weight, drug naïve, first episode schizophrenia and 60 healthy controls were enrolled. At baseline, the patient group had significantly higher proportions of Th17 cells and plasma levels of IFN-γ and IL-6 compared with the control group (p's<0.01). Within the patient group, there were significant positive relationships between the proportion of Th17 cells, plasma levels of IL-17, IFN- γ, IL-6 and the PANSS total score after controlling for potential confounding variables (p's<0.05). After 4 weeks of risperidone treatment, the proportion of Th17 cells decreased significantly (p<0.001), there was a significant positive relationship between the PANSS total score change rate and the change in proportion of Th17 cells (p=0.039). Patients with normal weight, drug naïve, first episode schizophrenia present activation of Th17 cells, which might be associated with therapeutic response after risperidone treatment.
Article
IL-1R antagonist-deficient (Il1rn(-/-)) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-β and IL-6, we found that Th17 cells developed normally in Il1rn(-/-)Il6(-/-) mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn(-/-)Il6(-/-) mice. We found that IL-21 production was increased in the lymph nodes of Il1rn(-/-) mice, naive Il6(-/-) CD4(+) T cells differentiated into Th17 cells when cultured with TGF-β and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-β or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4(+) T cells, and IL-1 inhibited TGF-β-induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell-specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell-specific transcription factors.
Article
Microglia act as sensors of inflammation in the central nervous system (CNS) and respond to many stimuli. Other key players in neuroinflammatory diseases are CD4(+) T helper cell (Th) subsets that characteristically secrete IFN-γ (Th1) or IL-17 (Th17). However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to modulate microglial phenotype and function is poorly understood. We therefore investigated the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. In vitro experiments wherein microglia were cultured in the presence of supernatants derived from polarized Th1 or Th17 cultures, revealed that Th1-associated factors could directly activate and trigger a proinflammatory M1-type gene expression profile in microglia that was cell-cell contact independent, whereas Th17 cells or its associated factors did not have any direct influence on microglia. To assess the effects of the key Th17 effector cytokine IL-17A in vivo we used transgenic mice in which IL-17A is specifically expressed in astrocytes. Flow cytometric and histological analysis revealed only subtle changes in the phenotype of microglia suggesting only minimal effects of constitutively produced IL-17A on microglia in vivo. Neither IL-23 signaling nor addition of GM-CSF, a recently described effector molecule of Th17 cells, changed the incapacity of Th17 cells to activate microglia. These findings demonstrate a potent effect of Th1 cells on microglia, however, the mechanism of how Th17 cells achieve their effect in CNS inflammation remains unclear.
Article
Immunoinflammatory mediated demyelination, the main pathological feature of multiple sclerosis (MS), is regularly accompanied by neurodegenerative processes, mostly in the form of axonal degeneration, which could be initiated by glutamate excitotoxicity. In the current study, the relationship between Th17 mediated inflammatory and excitotoxic events was investigated during an active phase of MS. Cerebrospinal fluid (CSF) of MS patients and control subjects was collected and IL-17A and glutamate levels were determined. IL-17A level was significantly higher in MS patients; whereas no statistically significant changes in glutamate concentrations were found. There was a direct correlation between IL-17A and glutamate levels; IL-17A levels were also associated with the neutrophil expansion in CSF and blood brain barrier disruption. However, IL-17A level and the number of neutrophils tended to fall with disease duration. The results suggest that Th17 cells might enhance and use glutamate excitotoxicity as an effector mechanism in the MS pathogenesis. Furthermore, Th17 immune response, as well as neutrophils, could be more important for MS onset rather than further disease development and progression, what could explain why some MS clinical trials, targeting Th17 cells in the later stage of the disease, failed to provide any clinical benefit. This article is protected by copyright. All rights reserved.