Auto-Reactive Th17-Cells Trigger Obsessive-Compulsive-Disorder Like Behavior in Mice With Experimental Autoimmune Encephalomyelitis

Kant, Ravi; Pasi, Shweta; Surolia, Avadhesha

doi:10.3389/fimmu.2018.02508

Cited by 14 publications

(10 citation statements)

References 67 publications

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“…The pathobiological relevance of the Th17 pathway is becoming increasingly apparent in various neuropsychiatric diseases, including major depression, obsessive–compulsive disorder, autism spectrum disorder, and, in particular, schizophrenia . Divergent lines of evidence suggest important functional implications of Th17 cells in schizophrenia pathophysiology, psychopathology, and treatment response .…”

Section: Discussionmentioning

confidence: 99%

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Subbanna

Shivakumar

Venugopal

et al. 2019

Psychiatry Clin Neurosci

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Aim: Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities and also immuno-dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells-mediated immuno-inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway.Methods: A total of 27 drug-naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)-1β, IL-6, IL-17A, IL-23, and IL-33, were also analyzed before and after treatment.Results: Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL-1β, IL-6, and IL-17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment. Conclusion:Our findings suggest possible immunomodulatory effects of antipsychotic medication on the critical regulators, such as IL-6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL-6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL-6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.Schizophrenia is a complex neurodevelopmental disorder with inadequately explained etiopathology. The notion that schizophrenia is a multisystem disorder has gained momentum in recent times. In addition to abnormalities in the central nervous system (CNS), immune system dysfunction has persistently been implicated in schizophrenia pathophysiology based on the data derived from genomic, transcriptomic, and proteomic studies. 1-3 The strength of this connection has further been enhanced by studies on schizophrenia showing close cross talk between the immune system and other pathologically relevant systems or pathways, such as the CNS, cardiovascular system, metabolic system, and the hypothalamicpituitary-adrenal axis.Altered expressions of immune parameters in the cerebrospinal fluid and post-mortem brain as well as findings correlating i...

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Section: Discussionmentioning

confidence: 99%

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Subbanna

Shivakumar

Venugopal

et al. 2019

Psychiatry Clin Neurosci

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“…In EAE mice, Th17 cells activate microglia to produce IL-6, IL-1β, and TNF-α. Then, IL-6 inhibits the synthesis of 5-HT by reducing tetrahydrobiopterin and TNF-α activates IDO, which breaks down Trp to reduce 5-HT level in the brain (119). In the in vitro culture of peripheral blood mononuclear cells isolated from MS patients, 5-HT reduces the production of IL-17 and IFN-γ from Th17 (27).…”

Section: Interaction Between 5-ht and Th17 And Tregsmentioning

confidence: 99%

Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases

et al. 2020

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Serotonin, also known as 5-hydroxytryptamine (5-HT) is a signaling mediator that regulates emotion, behavior, and cognition. Previous studies have focused more on the roles of 5-HT in the central nervous system (CNS). However, 5-HT also shares a strong relationship with the pathological cases of tumor, inflammation, and pathogen infection. 5-HT participates in tumor cell migration, metastatic dissemination, and angiogenesis. In addition, 5-HT affects immune regulation via different 5-HT receptors (5-HTRs) expressed immune cells, including both innate and adaptive immune system. Recently, drugs targeting at 5-HT signaling were tested to be beneficial in mouse models and clinical trials of multiple sclerosis (MS) and inflammatory bowel disease (IBD). Thus, it is reasonable to assume that 5-HT participates in the pathogenesis of autoimmune diseases. However, the underlying mechanism by 5-HT modulates the development of autoimmune diseases has not been fully understood. Based on our previous studies and pertinent literature, we provide circumstantial evidence for an essential role of 5-HT, especially the regulation of 5-HT on immune cells in the pathogenesis of autoimmune diseases, which may provide a new point cut for the treatment of autoimmune diseases.

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“…The compulsive-like HA strains demonstrate a persistent compulsive-like marble burying behavior ( 140 , 143 ). Most mouse models tested for marble burying as an indicator of compulsive-like behavior typically bury on an average 10–12 marbles ( 222 , 277 , 278 ). It is interesting to note that such burying attributes often correlate to anxiety-like and not compulsive-like responses.…”

Section: Excessive Nest-building and Marble Burying Fulfill The Validities For Compulsivity In Humansmentioning

confidence: 99%

Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity

Mitra

Bult‐Ito

2021

Front. Psychiatry

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Obsessive-compulsive disorder (OCD) and related disorders (OCRD) is one of the most prevalent neuropsychiatric disorders with no definitive etiology. The pathophysiological attributes of OCD are driven by a multitude of factors that involve polygenic mechanisms, gender, neurochemistry, physiological status, environmental exposures and complex interactions among these factors. Such complex intertwining of contributing factors imparts clinical heterogeneity to the disorder making it challenging for therapeutic intervention. Mouse strains selected for excessive levels of nest- building behavior exhibit a spontaneous, stable and predictable compulsive-like behavioral phenotype. These compulsive-like mice exhibit heterogeneity in expression of compulsive-like and other adjunct behaviors that might serve as a valuable animal equivalent for examining the interactions of genetics, sex and environmental factors in influencing the pathophysiology of OCD. The current review summarizes the existing findings on the compulsive-like mice that bolster their face, construct and predictive validity for studying various dimensions of compulsive and associated behaviors often reported in clinical OCD and OCRD.

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Auto-Reactive Th17-Cells Trigger Obsessive-Compulsive-Disorder Like Behavior in Mice With Experimental Autoimmune Encephalomyelitis

Cited by 14 publications

References 67 publications

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases

Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity

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