Engagement of tumor necrosis factor receptor 1 signals two diametrically opposed 
pathways: survival-inflammation and cell death. An additional switch decides, 
depending on the cellular context, between caspase-dependent apoptosis and RIP 
kinase (RIPK)-mediated necrosis, also termed necroptosis. We explored the 
contribution of both cell death pathways in TNF-induced systemic inflammatory 
response syndrome (SIRS). Deletion of apoptotic executioner caspases (caspase-3 
or -7) or inflammatory caspase-1 had no impact on lethal SIRS. However, deletion 
of RIPK3 conferred complete protection against lethal SIRS and reduced the 
amounts of circulating damage-associated molecular patterns. Pretreatment with 
the RIPK1 kinase inhibitor, necrostatin-1, provided a similar effect. These 
results suggest that RIPK1-RIPK3-mediated cellular damage by necrosis drives 
mortality during TNF-induced SIRS. RIPK3 deficiency also protected against cecal 
ligation and puncture, underscoring the clinical relevance of RIPK kinase 
inhibition in sepsis and identifying components of the necroptotic pathway that 
are potential therapeutic targets for treatment of SIRS and sepsis.