Impact of antipsychotic medication on IL-6/STAT3 signaling axis in peripheral blood mononuclear cells of drug-naive schizophrenia patients.
STAT3
Th17 pathway
antipsychotic treatment
inflammation
schizophrenia
Journal
Psychiatry and clinical neurosciences
ISSN: 1440-1819
Titre abrégé: Psychiatry Clin Neurosci
Pays: Australia
ID NLM: 9513551
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
29
05
2019
revised:
04
09
2019
accepted:
24
09
2019
pubmed:
7
10
2019
medline:
24
11
2020
entrez:
7
10
2019
Statut:
ppublish
Résumé
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. 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. 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. Our findings suggest possible immuno-modulatory 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.
Substances chimiques
Antipsychotic Agents
0
IL6 protein, human
0
Interleukin-6
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
64-69Subventions
Organisme : Wellcome Trust-DBT India Alliance Intermediate Clinical Fellowship
ID : IA/CPHI/15/1/502026
Organisme : National Health and Medical Research Council
ID : APP1156072
Organisme : National Health and Medical Research Council
ID : APP1059660
Informations de copyright
© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.
Références
Martins-de-Souza D, Gattaz WF, Schmitt A et al. Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2009; 259: 151-163.
Sanders AR, Drigalenko EI, Duan J et al. Transcriptome sequencing study implicates immune-related genes differentially expressed in schizophrenia: New data and a meta-analysis. Transl. Psychiatry 2017; 7: e1093.
Ripke S, Neale BM, Corvin A et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421-427.
Orlovska-Waast S, Kohler-Forsberg O, Brix SW et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: A systematic review and meta-analysis. Mol. Psychiatry 2019; 24: 869-887.
Pandey GN, Rizavi HS, Zhang H, Ren X. Abnormal gene and protein expression of inflammatory cytokines in the postmortem brain of schizophrenia patients. Schizophr. Res. 2018; 192: 247-254.
Fillman SG, Weickert TW, Lenroot RK et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume. Mol. Psychiatry 2016; 21: 1090-1098.
Kogan S, Ospina LH, Kimhy D. Inflammation in individuals with schizophrenia: Implications for neurocognition and daily function. Brain Behav. Immun. 2018; 74: 296-299.
Leboyer M, Berk M, Yolken RH, Tamouza R, Kupfer D, Groc L. Immuno-psychiatry: An agenda for clinical practice and innovative research. BMC Med. 2016; 14: 173.
Cho M, Lee TY, Kwak YB, Yoon YB, Kim M, Kwon JS. Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials. Aust. N. Z. J. Psychiatry 2019; 53: 742-759.
Debnath M. Adaptive immunity in schizophrenia: Functional implications of T cells in the etiology, course and treatment. J. Neuroimmune Pharmacol. 2015; 10: 610-619.
de Miranda AS, Zhang CJ, Katsumoto A, Teixeira AL. Hippocampal adult neurogenesis: Does the immune system matter? J. Neurol. Sci. 2017; 372: 482-495.
Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8180-8185.
Li Q, Zhou J, Cao X, Liu Q, Li W, Wang X. Clonal characteristics of T-cell receptor repertoires in violent and non-violent patients with schizophrenia. Front. Psych. 2018; 9: 403.
Craddock RM, Lockstone HE, Rider DA et al. Altered T-cell function in schizophrenia: A cellular model to investigate molecular disease mechanisms. PLoS One 2007; 2: e692.
Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: Mechanisms and implications. Schizophr. Bull. 2014; 40: 1412-1421.
Debnath M, Berk M. Functional implications of the IL-23/IL-17 immune axis in schizophrenia. Mol. Neurobiol. 2017; 54: 8170-8178.
Ding M, Song X, Zhao J et al. Activation of Th17 cells in drug naive, first episode schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014; 51: 78-82.
Li H, Zhang Q, Li N et al. Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia. Psychiatry Res. 2016; 246: 700-706.
Subbanna M, Shivakumar V, Talukdar PM et al. Role of IL-6/RORC/IL-22 axis in driving Th17 pathway mediated immunopathogenesis of schizophrenia. Cytokine 2018; 111: 112-118.
Sheehan DV, Lecrubier Y, Sheehan KH et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 1998; 59 (Suppl. 20): 22-33.
Andreasen N. The Scale for the Assessment of Negative Symptoms, The University of Iowa, Iowa City, IA, 1983 SANS.
Andreasen N. The Scale for the Assessment of Positive Symptoms, The University of Iowa, Iowa City, IA, 1984 SAPS.
Kant R, Pasi S, Surolia A. Auto-reactive Th17-cells trigger obsessive-compulsive-disorder like behavior in mice with experimental autoimmune encephalomyelitis. Front. Immunol. 2018; 9: 2508.
Slyepchenko A, Maes M, Kohler CA et al. T helper 17 cells may drive neuroprogression in major depressive disorder: Proposal of an integrative model. Neurosci. Biobehav. Rev. 2016; 64: 83-100.
Ahmad SF, Zoheir KMA, Ansari MA et al. Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Mol. Neurobiol. 2017; 54: 4390-4400.
Brown AS, Hooton J, Schaefer CA et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am. J. Psychiatry 2004; 161: 889-895.
Simoes LR, Sangiogo G, Tashiro MH et al. Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats. J. Psychiatr. Res. 2018; 100: 71-83.
Mandal M, Donnelly R, Elkabes S et al. Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring. Brain Behav. Immun. 2013; 33: 33-45.
Mandal M, Marzouk AC, Donnelly R, Ponzio NM. Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells. Brain Behav. Immun. 2011; 25: 863-871.
Yang XO, Pappu BP, Nurieva R et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008; 28: 29-39.
Mathur AN, Chang HC, Zisoulis DG et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J. Immunol. 2007; 178: 4901-4907.
Yang XO, Panopoulos AD, Nurieva R et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 2007; 282: 9358-9363.
Zhao M, Tan Y, Peng Q et al. IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation. Nat. Commun. 2018; 9: 583.
Davis J, Maes M, Andreazza A, McGrath JJ, Tye SJ, Berk M. Towards a classification of biomarkers of neuropsychiatric disease: From encompass to compass. Mol. Psychiatry 2015; 20: 152-153.
Romeo B, Brunet-Lecomte M, Martelli C, Benyamina A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: A meta-analysis. Int. J. Neuropsychopharmacol. 2018; 21: 828-836.
Kato TA, Monji A, Mizoguchi Y et al. Anti-inflammatory properties of antipsychotics via microglia modulations: Are antipsychotics a ‘fire extinguisher’ in the brain of schizophrenia? Mini Rev. Med. Chem. 2011; 11: 565-574.
Al-Amin MM, Nasir Uddin MM, Mahmud RH. Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin Psychopharmacol Neurosci. 2013; 11: 144-151.
Boozalis T, Teixeira AL, Cho RY, Okusaga O. C-reactive protein correlates with negative symptoms in patients with schizophrenia. Front. Public Health 2017; 5: 360.
Goldsmith DR, Haroon E, Miller AH, Strauss GP, Buckley PF, Miller BJ. TNF-alpha and IL-6 are associated with the deficit syndrome and negative symptoms in patients with chronic schizophrenia. Schizophr. Res. 2018; 199: 281-284.
Goldsmith DR, Haroon E, Miller AH et al. Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis. Brain Behav. Immun. 2019; 76: 268-274.
Bulzacka E, Boyer L, Schurhoff F et al. Chronic peripheral inflammation is associated with cognitive impairment in schizophrenia: Results from the multicentric FACE-SZ dataset. Schizophr. Bull. 2016; 42: 1290-1302.
Deakin B, Suckling J, Barnes TRE et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): A randomised, double-blind, placebo-controlled trial. Lancet Psychiatry 2018; 5: 885-894.
Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: An update. Schizophr. Bull. 2014; 40: 181-191.
Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: Lessons from genetics and therapeutic interventions. Immunity 2015; 43: 1040-1051.
Zambrano-Zaragoza JF, Romo-Martinez EJ, Duran-Avelar Mde J, Garcia-Magallanes N, Vibanco-Perez N. Th17 cells in autoimmune and infectious diseases. Int. J. Inflammation 2014; 2014: 651503.
Roeleveld DM, van Nieuwenhuijze AE, van den Berg WB, Koenders MI. The Th17 pathway as a therapeutic target in rheumatoid arthritis and other autoimmune and inflammatory disorders. BioDrugs 2013; 27: 439-452.
Toussirot E. The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm. Allergy Drug Targets 2012; 11: 159-168.
Mitsuyama K, Matsumoto S, Masuda J et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res. 2007; 27: 3749-3756.
Lee JJ, Kim HJ, Yang CS et al. A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non-small cell lung cancer. Mol. Ther. 2014; 22: 1254-1265.