Abstract
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). 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. 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. 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.
Highlights
Multiple sclerosis (MS) is a chronic and progressive inflammatory neurological disorder that is defined by central nervous sys tem (CNS) infiltration of autoreactive lymphocytes followed by demye lination and axonal injury [1]
We investigated the potential impact of miR-181a and -b on the pathogenesis of MS, using the established model for MS, experimental autoimmune encephalomyelitis (EAE) as well as in vitro culture systems and human brain tissues. miR-181a and -b expression levels together with their actions were analyzed in macrophage and T cell differentiation assays
Asking whether miR-181 overexpression might affect the differentiation of macrophages toward M1 or M2 phenotypes, we examined the expression of iNos, a key M1 marker, and arginase and Mrc1 as M2 markers in transfected cells. iNos expression was markedly reduced in miR-181a or -b overexpressing cells
Summary
Multiple sclerosis (MS) is a chronic and progressive inflammatory neurological disorder that is defined by central nervous sys tem (CNS) infiltration of autoreactive lymphocytes followed by demye lination and axonal injury [1]. To gain insight into molecular changes that occur in the CNS during disease, many studies have focused on transcript and protein expression levels within and around demyelinating lesions in MS [3,4,5]. These studies have shown altered expression of inflammatory as well as structural genes in the CNS of MS patients and have provided important information about the pathogenesis and potential therapeutic targets for disease [3]. We investigated the involvement of miR-181a and miR-181b in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE)
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