Etifoxine inhibits NLRP3 inflammasome activity in human and murine myeloid cells

Abstract

ABSTRACTBackgroundMultiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by immune-mediated demyelination within the central nervous system. 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.MethodsUsing bothin vivoandin vitroapproaches, this report investigated the use of a previously described ligand of the 18kDa translocator protein (TSPO), etifoxine, as an immunomodulator that inhibits inflammasome activation in primary human and murine macrophages and microglia. To further elucidate pathologic relevance in the MS context, investigations were also performedex vivousing peripheral blood mononuclear cells and purified CD14+monocytes derived from secondary progressive MS patients.ResultsHerein, it is demonstrated that etifoxine attenuated clinical symptoms in a mouse model of MS and significantly inhibited NLRP3 inflammasome activation in human and murine myeloid-derived cellsin vitroby 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 GABAAreceptor. 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.ConclusionsOur results suggest that the anti-inflammatory effects of etifoxine were mediated independently of its previously described mechanisms related to engagement with TSPO and the GABAAreceptor. Furthermore, we observed an anti-inflammatory effect in murine- and human-derived myeloid cells, as well as in MS patient-derived monocytes, which provides clinically relevant evidence to support the exploration of etifoxine as a possible form of therapy for secondary progressive MS.