Fig. 1: NLRP3 inflammasome activation pathway.

Activation of the NLRP3 inflammasome requires two steps. The first step is priming (Left), triggered by LPS or DAMPs/PAMPs, which are recognized by TLR4 and induce the expression of interleukin 1β (IL-1β), IL-18, and NLRP3 through the activation of the transcription factor nuclear factor κB (NF-κB). The second step is the activation of the NLRP3 inflammasome (right), which is induced by various PAMPs and DAMPs and can activate multiple upstream signaling events. These include K⁺ efflux, Cl^- efflux, lysosomal rupture, mitochondrial dysfunction, the production of reactive oxygen species (mtROS), and the release of oxidized mitochondrial DNA (mtDNA). The activation of NLRP3 stimulates the assembly and oligomerization of the NLRP3 inflammasome complex, which further activates caspase-1, leading to the cleavage of pro-IL-1β and pro-IL-18. GSDMD is also cleaved, and N-GSDMD inserts into the membrane, forming pores and inducing pyroptosis while releasing inflammatory cytokines such as IL-1β and IL-18. Additionally, the activation of the NLRP3 inflammasome activates caspase-8 and caspase-3, cleaving GSDME, with the cleaved N-GSDME forming pores in the cell membrane and releasing IL-1β and IL-18. LPS lipopolysaccharide, PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, TLR4 toll-like receptor 4, NF-κB nuclear factor-κB, ROS reactive oxygen species, mtDNA mitochondrial DNA, NLRP3 NOD-, LRR- and pyrin ___domain-containing protein 3, IL-1β interleukin 1β, IL-18 interleukin 18, NEK7 NIMA-related kinase 7, GSDMD gasdermin D, GSDME gasdermin E