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    Histone Deacetylase SIRT1 Mediates C5b-9-Induced Cell Cycle in Oligodendrocytes

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    Author
    Tatomir, A.
    Rao, G.
    Boodhoo, D.
    Vlaicu, S.I.
    Beltrand, A.
    Anselmo, F.
    Rus, V.
    Rus, H.
    Date
    2020
    Journal
    Frontiers in Immunology
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.3389/fimmu.2020.00619
    Abstract
    Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways. Copyright 2020 Tatomir, et. al.
    Sponsors
    This work was supported in part Veterans Administration Merit Award I01BX001458 and RO1 NS42011.
    Keyword
    C5b-9
    cell cycle
    cyclin D1
    oligodendrocyte
    SIRT1
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083899682&doi=10.3389%2ffimmu.2020.00619&partnerID=40&md5=9496d331526f226656869073dd3f5ca2; http://hdl.handle.net/10713/12766
    ae974a485f413a2113503eed53cd6c53
    10.3389/fimmu.2020.00619
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