Fiche publication
Date publication
août 2017
Journal
Journal of autoimmunity
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CARAPITO Raphaël
Tous les auteurs :
Saferding V, Puchner A, Goncalves-Alves E, Hofmann M, Bonelli M, Brunner JS, Sahin E, Niederreiter B, Hayer S, Kiener HP, Einwallner E, Nehmar R, Carapito R, Georgel P, Koenders MI, Boldin M, Schabbauer G, Kurowska-Stolarska M, Steiner G, Smolen JS, Redlich K, Blüml S
Lien Pubmed
Résumé
Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo. Deficiency of miR-146a induces deregulation of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) in synovial fibroblasts, leading to increased proliferation. In addition, loss of miR-146a shifts the metabolic state of fibroblasts towards glycolysis and augments the ability of synovial fibroblasts to support the generation of osteoclasts by controlling the balance of osteoclastogenic regulatory factors receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Bone marrow transplantation experiments confirmed the importance of miR-146a in the radioresistant mesenchymal compartment for the control of arthritis severity, in particular for inflammatory joint destruction. This study therefore identifies microRNA-146a as an important local epigenetic regulator of the inflammatory response in arthritis. It is a central element of an anti-inflammatory feedback loop in resident synovial fibroblasts, who are orchestrating the inflammatory response in chronic arthritis. MiR-146a restricts their activation, thereby preventing excessive tissue damage during arthritis.
Mots clés
Animals, Arthritis, genetics, Arthritis, Experimental, Bone Resorption, genetics, Cell Proliferation, Disease Models, Animal, Fibroblasts, metabolism, Gene Expression, Gene Expression Regulation, Humans, Joints, metabolism, Mice, Mice, Transgenic, MicroRNAs, genetics, RNA Interference, Synovial Membrane, cytology, TNF Receptor-Associated Factor 6, genetics, Tumor Necrosis Factor-alpha, genetics
Référence
J. Autoimmun.. 2017 Aug;82:74-84
