title: RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome.
abstract: 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.
authors.affiliation: Department for Molecular Biomedical Research, the Flanders Institute for Biotechnology (VIB), 9052 Ghent, Belgium.
authors.forename: Linde
authors.initials: L
authors.lastname: Duprez
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vandendriessche
authors.forename: Vera
authors.initials: V
authors.lastname: Goossens
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002429:Cecal Diseases / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D007211:Indoles; D014409:Tumor Necrosis Factor-alpha; C507699:necrostatin-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases