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.
Highlights
Though traditionally viewed as a T cell-mediated disease, the demonstration that selective B-cell depletion in patients with multiple sclerosis (MS) leads to substantial reductions in the development of new focal brain lesions and clinical relapses [1,2,3], establishes an important role for B cells in mediating disease activity
In order to dissect the molecular basis for the altered secretion of cytokines by MS B cells, we first compared cytokine profiles of activated B cells derived from untreated MS patients (n = 14; average age: 47.5762.28; female:male = 12:2) and healthy subjects (HS) (n = 13; average age: 47.2362.68; female:male = 11:2)
The screen (Table S2) suggested that expression levels of miR-132 (p = 0.0079) and miR-210 (p = 0.0362) were higher in MS B cells compared to HS B cells upon ‘dual B-cell antigen receptor (BCR)+ CD40 stimulation’, and that miR-142-5p expression was more highly expressed in MS B cells upon ‘CD40 stimulation’ (p = 0.0317)
Summary
Though traditionally viewed as a T cell-mediated disease, the demonstration that selective B-cell depletion in patients with multiple sclerosis (MS) leads to substantial reductions in the development of new focal brain lesions and clinical relapses [1,2,3], establishes an important role for B cells in mediating disease activity. Normal B cells are recognized to have the capacity to modulate T-cell responses through a number of antibodyindependent mechanisms, including the expression of pro- or anti-inflammatory B cell cytokines [4]. Abnormalities in these B cell cytokine responses, resulting in exaggerated activation of T cells (or failure to properly regulate them), are thought to be relevant to how B cells contribute to new MS relapses [5,6]. Relatively little is known about mechanisms that regulate normal B cell effector cytokine responses
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