A Novel MicroRNA-132-Surtuin-1 Axis Underlies Aberrant B-cell Cytokine Regulation in Patients with Relapsing-Remitting Multiple Sclerosis

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.

Antibody-independent functions of B cells: a focus on cytokines

“…For instance, increased expression of microRNA-132 by B cells from patients with multiple sclerosis was shown to upregulate their expression of lymphotoxin and TNF by suppressing sirtuin 1 expression 121 . Resveratrol, which is an activator of sirtuin 1, was found to normalize the expression of lymphotoxin and TNF by these B cells 121 . Further clarification of the mechanisms controlling cytokine production by B cells might help us to understand why these responses are sometimes deregulated in human autoimmune diseases.…”

Les microARN

“…L'utilisation de ces biopuces appliquée à différents tissus provenant de patients atteints de SEP a ainsi mis en évidence une altération de l'expression de nombreux miARN au cours de la maladie. La détection des miARN a été réalisée à partir de tissus (sang total [13,14], tissu nerveux [15,16], hippocampe [17]), de cellules (cellules mononucléées du sang [18][19][20], lymphocytes B [21][22][23] et T [11,20,[23][24][25][26], monocytes [27], microglie [27], cellules endothéliales [28,29]) ou de fluides extracellulaires (sérum/plasma [12,18,[30][31][32][33], LCR [34]). Nous répertorions de manière systématique dans cette revue, l'ensemble des données issues de la littérature concernant les miARN SYNTHÈSE REVUES miR-155 -/- [37]) sont résistantes à l'induction d'une EAE.…”

Introductory Chapter: Obesity—“OMICS” and Endocrinology

“…Deficiency of p53 is linked to cancer and is interpreted as if a poor regulation of Sirt1 is involved, predisposing for cancer. An interest in the nutritional modulation of obesity, with or without concomitant diabetes, has increased due to the effects of feeding patterns on Sirt1 and p53, being involved in the reciprocal nuclear-mitochondrial interactions, emerging mutations, as well as apoptosis (cell death) and/or responses encompassing permanent cellular senescence [35][36][37][38][39][40][41]. Sirt1 and its posttranscriptional impact on p53 [42,43] is heavily involved in the differentiation of adipocytes, as well as lipid metabolism in general [44][45][46][47][48], with their implications for abnormal Sirt1 deacetylation of p53, linked to lipid metabolism with its characteristic transformation of adipocytes and ensuing liver disease.…”

“…The LBPs, as well as leptin, are both upregulated in the obese, impinging on biological phenomena, like the expression of leptin, appetite, and obesity-provoked inflammatory reactions [36][37][38][39][40]. LPS has, since long, been demonstrated to affect the efflux of cholesterol via the liver X Receptors (LXR) and the ATP-binding cassette transporter 1 (ABCA1) [41,42] pathways, of which the latter is overriding the Sirt1-mediated impact on LXR-ABCA1 interactions.…”