title: A novel microRNA-132-sirtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis [corrected].
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.
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Yusei
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Ayman
authors.initials: A
authors.lastname: Rezk
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Hétoum
authors.initials: H
authors.lastname: Misirliyan
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Moore
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Nasr
authors.initials: N
authors.lastname: Farooqi
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Mayra
authors.initials: M
authors.lastname: Solis
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Lorna Galleguillos
authors.initials: LG
authors.lastname: Goiry
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: de Faria Junior
authors.affiliation: Deutsches Rheuma-Forschungszentrum, Leibniz Institute, Berlin, Germany.
authors.forename: Van Duc
authors.initials: VD
authors.lastname: Dang
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Colman
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Ajit Singh
authors.initials: AS
authors.lastname: Dhaunchak
authors.affiliation: Neuroimmunology Unit and Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gommerman
authors.affiliation: Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Deutsches Rheuma-Forschungszentrum, Leibniz Institute, Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Fillatreau
authors.affiliation: 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.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism*; D056564:Sirtuin 1 / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D008233:Lymphotoxin-alpha; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; C447939:SIRT1 protein, human; D056564:Sirtuin 1