NLRC4 Inflammasome-dependent Cell Death Occurs By An Ordered And Complementary Series Of Three Death Pathways And Determines Lethality In Mice

Inflammasomes are multiprotein complexes assembled by pattern recognition receptor (PRR) proteins in response to pathogen-associated molecular patterns (PAMPs)and sterile stress signals,whereas their 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-8dependent 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.Because of the high similarity among the subtype of inflammasomes,we would predict that all the inflammasome activation could lead to cell death through these death pathways,and this conclusion is not restricted to mouse system,but also applicable to human system.In addition,infection of non-propagative Salmonella-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.