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. 2022 Mar 28;15:2033–2050. doi: 10.2147/JIR.S352563

Figure 1.

Figure 1

The mechanism of pyroptosis. Pyroptosis involves canonical, non-canonical, and other pathways. NLRP3 inflammasome activation requires DAMPs or PAMPs to trigger the NF-κB-mediated upregulation the transcription of of NLRP3, pro-IL-1β and pro-IL-18. The formation and modification of NLRP3 inflammasomes by potassium efflux, the generation of reactive oxygen species (ROS), and cathepsin B released by lysosomal damage. Caspase-1 is triggered by the inflammasome and pro-IL-1β/pro-IL-18 is converted to IL-1β/IL-18 via caspase-1. Simultaneously, caspase-1 cleaves GSDMD and releases the GSDMD-NT. The GSDMD-NT fragment forms pores on the cytomembrane and promotes the secretion of the inflammatory cytokines, IL-1β and IL-18, resulting in plasma membrane rupture, cellular swelling, and eventually pyroptosis. LPS from gram-negative bacteria can access the cell cytoplasm via TLR4 receptor-mediated endocytosis and bind directly to caspase-4/5/11. Activated caspase-4/5/11 cleaves GSDMD into a GSDMD-NT fragment to induce cell membrane pore formation and initiate pyroptosis. This process can also cause NLRP3 activation by potassium efflux via nonselective pores. The cysteine protease (SpeB) from group A Streptococcus (GAP) can cleave GSDMA, triggering pyroptosis. The cleavage of GSDMA by the cysteine protease (SpeB), triggers pyroptosis during Streptococcus pyogenes infections. Active caspase-3 cleave GSDME and release GSDME-NT, thereby triggers pyroptosis. Caspase-8 can cleave GSDMD, GSDME, and GSDMC, to trigger pyroptosis.