Fig. 2: Schematic representation of pyroptosis pathways.

The canonical pathway upon sensing DAMPs, PAMPs or other cytosolic disturbances results in the recruitment and activation of caspase-1 either directly or through recruitment of the receptor protein ASC. Caspase-1 successively promotes maturation of the precursors of IL-1β and IL-18 into mature forms and cleaves GSDMD. The pore form domain (PFD) of GSDMD interacts with the plasma membrane to form GSDMD pores, resulting in the release of intracellular contents, including IL-1β and IL-18. The noncanonical pathway is initiated by the caspase-11 self-detection of cytosolic LPS in Gram-negative bacteria. Activated caspase-11 (caspase-4 or caspase-5 in humans) successively cleaves GSDMD and induces pyroptosis. The other pathway of pyroptosis can be engaged through mechanisms such as CASP8-GSDMD and CASP3-GSDME. In turn, activated caspase-3 cleaves GSDME to produce GSDMD-cNT, which forms pores in the plasma membrane and activates pyroptosis. The bacteria are recognized by TLR4, which signals via RIP1 to form a cell death complex consisting of RIP1, caspase-8, and FADD. Both this complex cleavage of GSDMD and activation through caspase 1/11 and GSDME cleavage via caspase-3 lead to cell membrane permeabilization and subsequent pyroptosis. In addition, neutrophil elastase (NE) is able to cleave GSDMD independently of caspase activity