PLoS ONE (Jan 2014)

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

  • Yusei Miyazaki,
  • Rui Li,
  • Ayman Rezk,
  • Hétoum Misirliyan,
  • Craig Moore,
  • Nasr Farooqi,
  • Mayra Solis,
  • Lorna Galleguillos Goiry,
  • Omar de Faria Junior,
  • Van Duc Dang,
  • David Colman,
  • Ajit Singh Dhaunchak,
  • Jack Antel,
  • Jennifer Gommerman,
  • Alexandre Prat,
  • Simon Fillatreau,
  • Amit Bar-Or,
  • CIHR/MSSC New Emerging Team Grant in Clinical Autoimmunity,
  • MSSRF Canadian B cells in MS Team

DOI
https://doi.org/10.1371/journal.pone.0105421
Journal volume & issue
Vol. 9, no. 8
p. e105421

Abstract

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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.