Initiation and perpetuation of NLRP3 inflammasome activation and assembly

Summary The NLRP 3 ( NOD ‐like receptor family, pyrin domain containing 3) inflammasome is a multiprotein complex that orchestrates innate immune responses to infection and cell stress through activation of caspase‐1 and maturation of inflammatory cytokines pro‐interleukin‐1β (pro‐ IL ‐1β) and pro‐ IL ‐18. Activation of the inflammasome during infection can be protective, but unregulated NLRP 3 inflammasome activation in response to non‐pathogenic endogenous or exogenous stimuli can lead to unintended pathology. NLRP 3 associates with mitochondria and mitochondrial molecules, and activation of the NLRP 3 inflammasome in response to diverse stimuli requires cation flux, mitochondrial Ca 2+ uptake, and mitochondrial reactive oxygen species accumulation. It remains uncertain whether NLRP 3 surveys mitochondrial integrity and senses mitochondrial damage, or whether mitochondria simply serve as a physical platform for inflammasome assembly. The structure of the active, caspase‐1‐processing NLRP 3 inflammasome also requires further clarification, but recent studies describing the prion‐like properties of ASC have advanced the understanding of how inflammasome assembly and caspase‐1 activation occur while raising new questions regarding the propagation and resolution of NLRP 3 inflammasome activation. Here, we review the mechanisms and pathways regulating NLRP 3 inflammasome activation, discuss emerging concepts in NLRP 3 complex organization, and expose the knowledge gaps hindering a comprehensive understanding of NLRP 3 activation.