TNF-induced lethality occurs independently of NLRP3 inflammasome signaling

Acute TNF-induced shock in mice is a classical model of systemic inflammatory response syndrome, yet the relative contribution of necroptotic and inflammasome pathways to lethality remains incompletely defined. While RIPK3/MLKL-dependent necroptosis is recognized as a key effector mechanism of TNF-induced lethality, the contribution of inflammasome signaling to this process has not been genetically resolved within a unified in vivo framework. Here, we combine single and double genetic ablation of Nlrp3 and Mlkl to define the relative contribution of canonical inflammasome activation and necroptotic execution in TNF-induced shock. We show that Nlrp3 -deficient mice remain fully susceptible to TNF-induced lethality despite reduced circulating IL-1β levels, whereas Mlkl -deficient mice are strongly protected. Importantly, Nlrp3/Mlkl double-deficient mice phenocopy Mlkl -deficient animals, demonstrating that loss of canonical NLRP3 inflammasome signaling does not modify survival outcomes in the absence of necroptotic execution. Together, these data establish RIPK3/MLKL-dependent necroptosis as the dominant determinant of TNF-induced lethality and demonstrate that canonical NLRP3 inflammasome signaling is dispensable for survival outcomes under sterile high-dose TNF conditions.