A novel mechanism for NLRP3 inflammasome activation

The NLRP3 inflammasome, as an important component of the innate immune system, plays vital roles in various metabolic disorders. It has been reported that the NLRP3 inflammasome can be activated by a broad range of distinct stimuli, such as K(+) efflux, mitochondrial dysfunction, lysosomal disruption and trans-Golgi disassembly, etc. However, there has been no well-established model for NLRP3 inflammasome activation so far, especially the underlying mechanisms for mitochondria in NLRP3 inflammasome activation remain elusive. Given that K(+) efflux is a widely accepted nexus for triggering activation of NLRP3 inflammasome in most previous studies, we sought to elucidate the role of mitochondria in K(+) efflux-induced NLRP3 inflammasome activation. Here, we demonstrated that inflammation activation by LPS evoked the expression of genes that involved in mitochondrial biogenesis and mitophagy, subsequently mitochondrial mass and mitochondrial membrane potential were also elevated, suggesting the contribution of mitochondria in inflammatory responses. Moreover, we inhibited mitochondrial biogenesis by silencing Tfam and genetic ablation of Tfam abolished the NLRP3 inflammasome activation induced by K(+) efflux via release of mitochondrial DNA (mtDNA), as deprivation of cellular mtDNA by EtBr treatment could reverse inflammasome activation induced by K(+) efflux. Collectively, we reveal that mtDNA release induced by K(+) efflux in macrophages activates NLRP3 inflammasome, and propose that mitochondria may serve as a potential therapeutic target for NLRP3 inflammasome-related diseases.