Figure 1.

Immunologically silent versus inflammatory apoptosis. (a) During apoptosis, active caspase-3 and −7 cleave and activate the plasma membrane glycoprotein pannexin-1 to enhance clearance of apoptotic cells. Caspase-8 can directly cleave Gasdermin D (GSDMD) to induce cell lysis, but this is counteracted by caspase-3/7. Caspase-3 processes Gasdermin E (GSDME) and liberates its pore-forming domain, but this does not drive cell lysis. Whether endosomal sorting complexes required for transport (ESCRT)-mediated membrane repair suppresses GSDMD or GSDME-driven pore formation during apoptosis is unknown. (b) Infection with certain pathogens or exposure to chemotherapeutic drugs may trigger enhanced caspase-8 activation, and induce the expression of NLRP3 (NLR family, pyrin domain containing 3) and pro-interleukin (IL)-1β. This promotes caspase-8-driven GSDMD activation and resultant cell lysis. Furthermore, pannexin-1 activation promotes NLRP3 inflammasome assembly via potassium efflux, driving IL-1β and GSDMD processing by caspase-1.

Casp8, caspase-8; Casp9, caspase-9; Casp1, caspase-1, Casp3, caspase-3;Casp7, caspase-7.