RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome

Immunity. 2011 Dec 23;35(6):908-18. doi: 10.1016/j.immuni.2011.09.020.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspases / metabolism
  • Cecal Diseases / genetics
  • Cecal Diseases / pathology
  • Gene Deletion
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology
  • Indoles / administration & dosage
  • Indoles / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis*
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Systemic Inflammatory Response Syndrome / enzymology*
  • Systemic Inflammatory Response Syndrome / genetics
  • Systemic Inflammatory Response Syndrome / mortality
  • Tumor Necrosis Factor-alpha / pharmacology


  • Imidazoles
  • Indoles
  • Tumor Necrosis Factor-alpha
  • necrostatin-1
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspases