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PLoS One. 2014 Aug 19;9(8):e105421. doi: 10.1371/journal.pone.0105421. eCollection 2014.

A novel microRNA-132-sirtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis [corrected].

Author information

1
Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
2
Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
3
Deutsches Rheuma-Forschungszentrum, Leibniz Institute, Berlin, Germany.
4
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
5
Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
6
Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; Experimental Therapeutics Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Erratum in

  • PLoS One. 2014;9(9):e109041.

Abstract

Clinical trial results demonstrating that B-cell depletion substantially reduces new relapses in patients with multiple sclerosis (MS) have established that B cells play a role in the pathophysiology of MS relapses. The same treatment appears not to impact antibodies directed against the central nervous system, which underscores the contribution of antibody-independent functions of B cells to disease activity. One mechanism by which B cells are now thought to contribute to MS activity is by over-activating T cells, including through aberrant expression of B cell pro-inflammatory cytokines. However, the mechanisms underlying the observed B cell cytokine dysregulation in MS remain unknown. We hypothesized that aberrant expression of particular microRNAs might be involved in the dysregulated pro-inflammatory cytokine responses of B cells of patients with MS. Through screening candidate microRNAs in activated B cells of MS patients and matched healthy subjects, we discovered that abnormally increased secretion of lymphotoxin and tumor necrosis factor α by MS B cells is associated with abnormally increased expression of miR-132. Over-expression of miR-132 in normal B cells significantly enhanced their production of lymphotoxin and tumor necrosis factor α. The over-expression of miR-132 also suppressed the miR-132 target, sirtuin-1. We confirmed that pharmacological inhibition of sirtuin-1 in normal B cells induces exaggerated lymphotoxin and tumor necrosis factor α production, while the abnormal production of these cytokines by MS B cells can be normalized by resveratrol, a sirtuin-1 activator. These results define a novel miR-132-sirtuin-1 axis that controls pro-inflammatory cytokine secretion by human B cells, and demonstrate that a dysregulation of this axis underlies abnormal pro-inflammatory B cell cytokine responses in patients with MS.

PMID:
25136908
PMCID:
PMC4138149
DOI:
10.1371/journal.pone.0105421
[Indexed for MEDLINE]
Free PMC Article

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