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

Nature Immunology volume 13, pages 954–962 (2012)Cite this article

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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.

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Figure 1: Prolonged survival of Ifnar1−/− mice to S. Typhimurium infection.
Figure 2: Ifnar1−/− macrophages are resistant to S. Typhimurium–induced cell death.
Figure 3: Cytokine secretion and inflammasome activation are not impaired in Ifnar1−/− macrophages.
Figure 4: Type I interferon induces necroptosis in S. Typhimurium–infected macrophages.
Figure 5: Infection of macrophages with S. Typhimurium leads to type I interferon–dependent phosphorylation of RIP1 and RIP3.
Figure 6: Engagement of IFNAR leads to necroptosis.
Figure 7: Inhibition of necroptosis in macrophages leads to less macrophage death and enhanced bacterial control.

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Acknowledgements

We thank K. Murali-Krishna (Emory University) for Ifnar−/− mice; V. Dixit (Genentech) for Rip3−/− mice; B. Beutler (The University of Texas Southwestern Medical Center) for the L929-ISRE cell line; and S. Thurston for technical help. Supported by the Canadian Institutes of Health Research (S.S.), the Ontario Institute of Cancer Research (L.K.) and the National Research Council of Canada.

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Author notes

  1. Nirmal Robinson & Rebecca Mulligan

    Present address: Present addresses: Institute for Medical Microbiology, Immunology and Hygiene, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany (N.R.), and Health Sciences North, Sudbury, Canada (R.M.).,

Authors and Affiliations

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

    Nirmal Robinson, Scott McComb, Rebecca Mulligan, Renu Dudani, Lakshmi Krishnan & Subash Sad

  2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada

    Nirmal Robinson, Scott McComb, Rebecca Mulligan, Lakshmi Krishnan & Subash Sad

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  1. Nirmal Robinson
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Contributions

N.R., S.M., R.M. and R.D. performed experiments and analyzed the data. N.R., S.M., L.K. and S.S. designed the experiments and wrote the manuscript. S.S. and L.K. conceptualized the project, obtained research funding and provided reagents.

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Correspondence to Subash Sad.

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Robinson, N., McComb, S., Mulligan, R. et al. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat Immunol 13, 954–962 (2012). https://doi.org/10.1038/ni.2397

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