The proinflammatory cell death pyroptosis is triggered when pattern recognition receptors detect danger- or pathogen-associated molecular patterns, which initiate the assembly of multiprotein complexes called inflammasomes. Inflammasome activation leads to the activation of proinflammatory caspases such as caspase-1. Active caspase-1 cleaves the pore-forming protein Gasdermin D (GSDMD) in its linker region to liberate the N-terminal domain (GSDMDNT) from the autoinhibition by the C-terminal domain. Generated GSDMDNT targets the plasma membrane, where it oligomerizes and forms large pores. Pore formation allows intracellular protein release such as cleaved IL-1b and IL-18, which are proinflammatory cytokines processed by caspase-1. Sustained pore formation leads to complete cell lysis, and an indiscriminately intracellular content leakage that drives to pyroptosis. Since pyroptosis is highly proinflammatory, it is tempting to speculate that cells possess intracellular mechanisms to dampen cell lysis and avoid hyperinflammation. Indeed, we demonstrated that the endosomal sorting complexes required for transport (ESCRT) machinery negatively regulates GSDMD-induced cell death by removing GSDMD pores from the plasma membrane in form of ectosomes. Opposite to pyroptosis, apoptosis is traditionally viewed as immunologically silent. However, emerging studies have shown that apoptosis triggers inflammatory signaling pathways such as NLRP3 inflammasome activation by an unknown mechanism. Here, we propose that caspase-3/-7-induced cleavage of the plasma membrane channel pannexin-1 triggers potassium efflux to drive NLRP3 inflammasome activation in extrinsic and intrinsic apoptosis, whereas pannexin-1 is dispensable for NLRP3 inflammasome activation during pyroptosis. Remarkably, we also found that apoptotic caspase-8, equally as caspase-1, directly cleaves GSDMD, liberating the GSDMDNT to drive lytic cell death during extrinsic apoptosis. Paradoxically, our findings suggest that caspase-8-induced caspase-3 activation downregulates GSDMD-dependent cell lysis by cleaving GSDMD within the GSDMDNT. Interestingly, we observed caspase-8-induced GSDMD processing during RIPK1-dependent extrinsic apoptosis, but not when caspase-8 was activated by other signaling pathways, and exclusively when caspase-8 is autoprocessed. We next sought to uncover the physiological relevance of caspase-8-induced GSDMD activation in vivo. Remarkably, we observed a GSDMD-dependent, but caspase-1-independent mice susceptibility to TNF-induced lethality. Since cell death has also been associated with pathogen clearance, we investigated whether caspase-8-driven pyroptosis contributes to bacterial clearance upon Yersinia infection, a pathogen reported to trigger extrinsic apoptosis in macrophages. Indeed, mice lacking GSDMD displayed elevated bacterial burdens and susceptibility to Yersinia infection compared to WT counterparts. We also demonstrated that another gasdermin protein family member, Gasdermin E (GSDME), drives pyroptosis in neutrophils, but not in macrophages. Remarkably, naïve neutrophils lacking GSDME do not undergo spontaneous apoptosis in vitro. We also show that, opposite to GSDMD-dependent IL-1b release reported in macrophages, GSDME-dependent cell death allows IL-1b release in neutrophils, and promotes Yersinia restriction in vivo.