NLRC4 inflammasome-dependent cell death occurs by a complementary series of three death pathways and determines lethality in mice.

Inflammasome is an innate immune defense mechanism, but its overactivation can lead to host death. Here, we show that cell death dictates mouse death caused by NLRC4 inflammasome overactivation. To execute NLRC4-dependent cell death, three death pathways complement each other in a specific order: Pyroptosis pathway requiring caspase-1 and GSDMD is the default path; impairment of it initiates ASC-mediated caspase-8–dependent apoptosis; when these two pathways are blocked, caspase-1 triggers intrinsic apoptotic pathway. Blocking one or two of these death pathways inhibits induction of various cytokines and lipid mediators, but mice still succumb, and only genetic deletions that block all death paths prevent NLRC4-mediated cell death, tissue damage, and mice death. In addition, infection of nonpropagative -caused mice death is attenuated by blocking these death pathways. Thus, to reduce the lethality of infection-related diseases, preventing cell death might be necessary when propagation of infected pathogen was controlled by other means.