Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity

Department of Neurology, The Ohio State University, 395 West 12th Avenue Columbus, OH 43210, USA.
Brain (Impact Factor: 9.2). 11/2011; 134(Pt 12):3578-89. DOI: 10.1093/brain/awr262
Source: PubMed


Pro-inflammatory T cells mediate autoimmune demyelination in multiple sclerosis. However, the factors driving their development and multiple sclerosis susceptibility are incompletely understood. We investigated how micro-RNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T-cell differentiation in multiple sclerosis. miR-128 and miR-27b were increased in naïve and miR-340 in memory CD4(+) T cells from patients with multiple sclerosis, inhibiting Th2 cell development and favouring pro-inflammatory Th1 responses. These effects were mediated by direct suppression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and interleukin-4 (IL4) expression, resulting in decreased GATA3 levels, and a Th2 to Th1 cytokine shift. Gain-of-function experiments with these micro-RNAs enhanced the encephalitogenic potential of myelin-specific T cells in experimental autoimmune encephalomyelitis. In addition, treatment of multiple sclerosis patient T cells with oligonucleotide micro-RNA inhibitors led to the restoration of Th2 responses. These data illustrate the biological significance and therapeutic potential of these micro-RNAs in regulating T-cell phenotypes in multiple sclerosis.

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Available from: Sean E. Lawler
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    • "Total RNA was isolated by the Trizol method (Invitrogen, Carlsbad, CA, USA) and heparinase treated as described [19]. Primary MCT miRNA expression profiling was performed at the OSU Nucleic Acid Shared Resource using the TaqMan Array Human miRNA Panel (Human A Cards, v.2, Applied Biosystems, Foster City, CA, USA) as described previously [20]. This panel assays the expression of 377 human miRNAs, 151 of whose mature sequences are 100% conserved between human and dog (Sanger miRBase v.12). "
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    • "Guerau-de-Arellano et al. [28] have shown that miRNAs such as miR-128 and miR-27b increased in naive T cells and miR-340 in memory CD4 + T cells of MS patients are involved in differentiation of pathogenic T cells. Changes in the expression of these miRNAs inhibited Th2 differentiation and induced pathogenic Th1 differentiation in mouse and human cells, suggesting that these miRNAs could regulate T-cell phenotypes in MS and thus have therapeutic potentials [28]. Other studies on miRNA in MS were listed in Table 1 and explained below. "
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    • "It has been suggested that miR-155 expression in dendritic cells is required for development of inflammatory Th17 cells (O'Connell et al., 2010). miR-155 is also associated with several autoimmune diseases such as EAE (Murugaiyan et al., 2011), arthritis (Kurowska-Stolarska et al., 2011), systemic lupus erythematosus (SLE) (Leng et al., 2011), chronic gastritis, and colitis (Oertli et al., 2011). In contrast to these reports, expression of miR- 155 has been found to negatively regulate Th17 cells in acute coronary syndrome patients (Yao et al., 2011). "
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