The expanding role of the NLRP3 inflammasome from periodic fevers to therapeutic targets

Abstract

Understanding and treating inflammation has proven a formidable challenge. The initiator and central motor of inflammation, the protein NLRP3, is an innate immune sentinel and nonspecific sensor of cellular perturbation. A wide array of inflammatory triggers prompts the formation of an NLRP3 ‘inflammasome’ complex, leading to inflammatory interleukin-1 family cytokine release and pyroptotic cell death. Since gain-of-function mutations in NLRP3 were demonstrated to cause a rare autoinflammatory disease termed cryopyrin-associated periodic syndrome, NLRP3 has emerged as key mediator of inflammation in mouse models for many common diseases, including atherosclerosis, Alzheimer’s disease and gout. But even though small-molecule NLRP3 modulators have entered clinical development, many aspects of NLRP3 activation and regulation in humans remain relatively unclear. This Review summarizes the current understanding of the molecular mechanisms that drive NLRP3 inflammasome activation and regulation, and discusses emerging targeting strategies. Understanding these processes can guide precision medicine approaches aimed at mitigating NLRP3-driven pathologies. Latz et al. review the molecular mechanisms that drive NLRP3 inflammasome activation and regulation, and discuss emerging targeting strategies.