title: Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium.
abstract: Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1(-/-) mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1(-/-) macrophages, they were highly resistant to S. Typhimurium-induced cell death. Specific inhibition of the kinase RIP1 or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response.
authors.affiliation: National Research Council of Canada-Institute for Biological Sciences, Ottawa, Canada.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Robinson
authors.forename: Scott
authors.initials: S
authors.lastname: McComb
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mulligan
authors.forename: Renu
authors.initials: R
authors.lastname: Dudani
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
mesh_terms: D000818:Animals; D017209:Apoptosis; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057131:Immune Evasion; D058847:Inflammasomes; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity*; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; C508032:Ifnar1 protein, mouse; D058847:Inflammasomes; D007370:Interferon Type I; C490620:Ralbp1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse