MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis

Abstract

BackgroundMicroRNAs have emerged as an important class of modulators of gene expression. These molecules influence protein synthesis through translational repression or degradation of mRNA transcripts. Herein, we investigated the potential role of miR-142a isoforms, miR-142a-3p and miR-142a-5p, in the context of autoimmune neuroinflammation.MethodsThe expression levels of two mature isoforms of miR-142 were measured in the brains of patients with multiple sclerosis (MS) and the CNS tissues from mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Expression analyses were also performed in mitogen and antigen-stimulated splenocytes, as well as macrophages and astrocytes using real-time RT-PCR. The role of the mature miRNAs was then investigated in T cell differentiation by transfection of CD4+ T cells, followed by flow cytometric analysis of intracellular cytokines. Luciferase assays using vectors containing the 3′UTR of predicted targets were performed to confirm the interaction of miRNA sequences with transcripts. Expression of targets were then analyzed in activated splenocytes and MS/EAE tissues.ResultsExpression of miR-142-5p was significantly increased in the frontal white matter from MS patients compared with white matter from non-MS controls. Likewise, expression levels of miR-142a-5p and miR-142a-3p showed significant upregulation in the spinal cords of EAE mice at days 15 and 25 post disease induction. Splenocytes stimulated with myelin oligodendrocyte glycoprotein (MOG) peptide or anti-CD3/anti-CD28 antibodies showed upregulation of miR-142a-5p and miR-142a-3p isoforms, whereas stimulated bone marrow-derived macrophages and primary astrocytes did not show any significant changes in miRNA expression levels. miR-142a-5p overexpression in activated lymphocytes shifted the pattern of T cell differentiation towards Th1 cells. Luciferase assays revealed SOCS1 and TGFBR1 as direct targets of miR-142a-5p and miR-142a-3p, respectively, and overexpression of miRNA mimic sequences suppressed the expression of these target transcripts in lymphocytes. SOCS1 levels were also diminished in MS white matter and EAE spinal cords.ConclusionsOur findings suggest that increased expression of miR-142 isoforms might be involved in the pathogenesis of autoimmune neuroinflammation by influencing T cell differentiation, and this effect could be mediated by interaction of miR-142 isoforms with SOCS1 and TGFBR-1 transcripts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0832-7) contains supplementary material, which is available to authorized users.

A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

“…TGFBR1 has been shown in several studies to be implicated in AD pathogenesis (Caraci et al, 2012;Chen, Ke, Lu, Qiu, & Peng, 2015;Flanders, Lippa, Smith, Pollen, & Sporn, 1995;Lippa, Flanders, Kim, & Croul, 1998;Tesseur et al, 2006;Wyss-Coray et al, 2002). The regulation of TGFBR1 expression by miR-142-3p has been experimentally confirmed at mRNA and protein levels in previous studies (Talebi et al, 2017;Yang et al, 2017). Our differential expression analysis for all miR-142-3p target genes demonstrated that TGFBR1 was significantly downregulated in miR-142-3p overexpressing human iPS-derived NPCs and the top target gene upregulated in the hippocampus of miR-142 KO mice.…”

Differential Expression of miRNAs and Behavioral Change in the Cuprizone-Induced Demyelination Mouse Model

“…Many miRNAs have functioned as important regulators of the immune system [33,34,[43][44][45][46]. In particular, miR-155 is known to be a crucial regulator orchestrating the role of numerous acquired and native immune cell populations.…”

Genipin alleviates high‐fat diet‐induced hyperlipidemia and hepatic lipid accumulation in mice via miR‐142a‐5p/SREBP‐1c axis

“…For example, miR-33 reduces SREBP-1c protein expression and deletion of miR-33 results in marked worsening of HFD-induced obesity and liver steatosis in mice [54]. Only a few reports indicated that miR-142a-5p is involved in vascular development and integrity [55], neutrophil development [56], and inflammation and T-cell differentiation [57]. Currently, the physiological roles of miR-142a-5p have not been well studied.…”

“…Currently, the physiological roles of miR-142a-5p have not been well studied. Only a few reports indicated that miR-142a-5p is involved in vascular development and integrity [55], neutrophil development [56], and inflammation and T-cell differentiation [57]. Our results extended the recognition of miR-142a-5p functions and given the importance of SREBP-1c in the control of lipid homeostasis, suppression of SREBP-1c by miR-142a-5p would establish a connection among diverse pathophysiological conditions such as hyperlipidemia, cardiovascular remodeling, and innate immunity.…”