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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / metabolism*
  • Immune Evasion
  • Inflammasomes
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Macrophage Activation
  • Macrophages / immunology
  • Macrophages / microbiology
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Salmonella Infections, Animal / immunology*
  • Salmonella Infections, Animal / metabolism
  • Salmonella Infections, Animal / microbiology
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / pathogenicity*
  • Signal Transduction


  • GTPase-Activating Proteins
  • Ifnar1 protein, mouse
  • Inflammasomes
  • Interferon Type I
  • Ralbp1 protein, mouse
  • Receptor, Interferon alpha-beta
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse