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Microrna-181 Variants Regulate T Cell Phenotype in the Context of Autoimmune Neuroinflammation Publisher



Ghorbani S1, 2 ; Talebi F1 ; Chan WF3 ; Masoumi F1 ; Vojgani M1 ; Power C3, 4 ; Noorbakhsh F1
Authors
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Authors Affiliations
  1. 1. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Shefa Neuroscience Research Center, Khatam Al-Anbia Hospital, Tehran, Iran
  3. 3. Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada
  4. 4. Multiple Sclerosis Centre, University of Alberta, Edmonton, AB, Canada

Source: Frontiers in Immunology Published:2017


Abstract

Background: Recent studies have revealed that multiple sclerosis (MS) lesions have distinct microRNA (miRNA) expression profiles. miR-181 family members show altered expression in MS tissues although their participation in MS pathogenesis remains uncertain. Herein, we investigated the involvement of miR-181a and miR-181b in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Methods: miR-181a and -b levels were measured in the central nervous system (CNS) of patients with MS and mice with EAE as well as relevant leukocyte cultures by real-time RT-PCR. To examine the role of the miRNAs in leukocyte differentiation and function, miR-181a and -b mimic sequences were transfected into cultured primary macrophages and purified CD4 + T cells which were then analyzed by RT-PCR and flow cytometry. Luciferase reporter assays were performed to investigate the interaction of miR-181a and -b with the 3'-UTR of potential target transcripts, and the expression of target genes was measured in the CNS of EAE mice, activated lymphocytes, and macrophages. Results: Expression analyses revealed a significant decrease in miR-181a and -b levels in brain white matter from MS patients as well as in spinal cords of EAE mice during the acute and chronic phases of disease. Suppression of miR-181a was observed following antigen-specific or polyclonal activation of lymphocytes as well as in macrophages following LPS treatment. Overexpression of miR-181a and -b mimic sequences reduced proinflammatory gene expression in macrophages and polarization toward M1 phenotype. miR-181a and -b mimic sequences inhibited Th1 generation in CD4+ T cells and miR-181a mimic sequences also promoted Treg differentiation. Luciferase assays revealed Suppressor of mothers against decapentaplegic 7 (Smad7), as a direct target of miR-181a and -b. Conclusion: Our data highlight the anti-inflammatory actions of miR-181a and -b in the context of autoimmune neuroinflammation. miR-181a and -b influence differentiation of T helper cell and activation of macrophages, providing potential therapeutic options for controlling inflammation in MS. © 2017 Ghorbani, Talebi, Chan, Masoumi, Vojgani, Power and Noorbakhsh.
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