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Nat Immunol. 2012 Oct;13(10):954-62. doi: 10.1038/ni.2397. Epub 2012 Aug 26.

Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium.

Author information

1
National Research Council of Canada-Institute for Biological Sciences, Ottawa, Canada.

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.

PMID:
22922364
PMCID:
PMC4005791
DOI:
10.1038/ni.2397
[Indexed for MEDLINE]
Free PMC Article

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