The effects of etifoxine on the NLRP3 inflammasome and its relevance in elucidating the pathophysiology of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by immune-mediated demyelination within the central nervous system. Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation has been previously reported as a possible pathophysiological contributor to microglial activation and oligodendroglial loss in MS, particularly in progressive forms of the disease. Herein, it is demonstrated that etifoxine, a translocator protein (TSPO) ligand, attenuates the clinical symptoms in a mouse model of MS and significantly inhibits NLRP3 inflammasome activation in human and murine myeloid-derived cells in vitro by decreasing inflammasome-associated genes and inflammatory cytokine production. These anti-inflammatory effects of etifoxine were mediated independently of its previously described mechanisms related to engagement with TSPO and the GABAA receptor. Furthermore, we observed a similar anti-inflammatory effect of etifoxine on MS patient-derived monocytes, which provides clinical relevance for the investigation of etifoxine as a potential therapeutic in progressive MS. Lastly, through the use of a gene array, we identified multiple signalling pathways in order to elucidate a novel mechanism whereby etifoxine may be inhibiting NLRP3 inflammasome activation.