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MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination.

Abstract

MicroRNAs (miRNAs) are an emerging group of short, noncoding RNAs that play an important role in regulating expression of classical genes. Thus far little is known about their role in autoimmune demyelination. In this study, we analyzed changes in the miRNA profile in CD4(+) T cells that occurred during the recognition of the myelin autoantigen, MOG(35-55). We found that, both in vivo and in vitro, myelin antigen stimulation resulted in significant up-regulation of miR-301a, miR-21, and miR-155. Furthermore, these three miRNAs were overexpressed in T cells infiltrating the CNS in animals with experimental autoimmune encephalomyelitis. Use of specific miRNA antagonists, antagomirs, revealed that miR-301a contributed to the development of the T-helper type 17 subset via targeting the IL-6/23-STAT3 pathway. This contribution appeared to be mediated by the miR-301a effect on the expression of the PIAS3, a potent inhibitor of the STAT3 pathway. Manipulation of miR-301a levels or PIAS3 expression in myelin-specific CD4(+) T cells led to significant changes in the severity of experimental autoimmune encephalomyelitis. Thus, we have identified a role of miR-301a in regulating the function of myelin-reactive T-helper type 17 cells, supporting a role for miR-301a and PIAS3 as candidates for therapeutic targets for controlling of autoimmune demyelination.

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  • Authors

    Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, Selmaj KW

    Source

    Proceedings of the National Academy of Sciences of the United States of America 109:20 2012 May 15 pg E1248-57

    MeSH

    Animals
    Blotting, Western
    CD4-Positive T-Lymphocytes
    DNA Primers
    DNA-Binding Proteins
    Encephalomyelitis, Autoimmune, Experimental
    Flow Cytometry
    Gene Expression Regulation
    Luciferases
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    MicroRNAs
    Protein Inhibitors of Activated STAT
    Real-Time Polymerase Chain Reaction
    STAT3 Transcription Factor
    Signal Transduction
    Statistics, Nonparametric
    Th17 Cells

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22517757