Fig. 4

Activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome involves two steps. The first step, priming (left panel) is triggered by cytokines or PAMPs/DAMPs acting through TLRs and leads to pro-IL-1β and pro-IL-18 production. The second step (right panel) is NLRP3 inflammasome assembly and activation, which is triggered by several signals, including K⁺ efflux, Ca²⁺ influx, extracellular ATP, lysosomal cathepsin and ROS. Increased intracellular Ca²⁺ due to ER stress causes mitochondrial damage and ROS release whereas ruptured lysosomes release cathepsin. This triggers the assembly and activation of NLRP3 inflammasome. Activation of caspase-1 results in the proteolytic cleavage of pro-IL-1β and pro-IL-18 and secretion of active IL-1β and IL-18. In addition, NLRP3 inflammasome activation results in cleavage of GSDMD. The N-terminal fragment (N-GSDMD) generated is incorporated into the cell membrane and forms pores that mediate pyroptosis. ASC, apoptosis-associated speck-like protein containing a CARD; CARD9, caspase recruitment domain-containing protein 9; DAMP, danger associated molecular pattern; GSDMD, Gasdermin D; IL-1β, interleukin 1β; IL-1R, interleukin receptor 1; NF-κB, nuclear factor kappa B; NLRP3, NACHT, LRR- and pyrin domains-containing protein 3; P2X, purinoceptor 7; PAMP, pathogen associated molecular pattern; ROS, reactive oxygen species; TLR, toll-like receptor; TNF, tumor necrosis factor; TNFR, TNF receptor. Created with BioRender.com