Usnoflast: A cutting-edge NLRP3 inhibitor attenuates colonic inflammation across diverse immunopathology

NLR (Nod-like receptor) family pyrin domain containing protein 3 (NLRP3) inflammasome activation is key component of innate immune response and is implicated in many autoimmune conditions. Usnoflast is a novel, selective NLRP3-inflammasome inhibitor and is currently in Phase II for various indications including Ulcerative colitis. Here, we report the effect of usnoflast in several experimental models of intestinal inflammation, some of them for the first time for any NLRP3 inhibitor, which involves both innate and adaptive immune mechanisms. Usnoflast suppressed lipopolysaccharide (LPS), and ATP induced interleukin (IL)-1β and IL-18 production in vivo with ID₅₀ of 0.18 and 0.13 mg/kg indicating a potent inhibition of NLRP3 inflammasome activation. Usnoflast treatment ameliorated inflammation induced by dextran sodium sulfate (DSS) which was associated with suppression of NLRP3 target genes IL-1β and 18 in the colon tissues. Microarray analysis of colon tissues revealed modulation of several genes involved in biological processes such as inflammatory response, neutrophil chemotaxis, innate immune response, which were markedly altered by the treatment. Furthermore, for the first time, an NLRP3 inhibitor was evaluated in Salmonella typhimurium induced enterocolitis where, usnoflast treatment was able to prevent colonic inflammation. Moreover, usnoflast treatment was able to suppress the TNBS and chronic DSS-induced colon inflammation, which are diseases driven by cell mediated immunity involving either T helper (Th)-1 or a mixed Th1 and Th2 cell types. These data clearly demonstrate the therapeutic potential of usnoflast against intestinal inflammation involving diverse immunopathogenesis.