Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling

Kipyegon Kitur, Sarah Wachtel, Armand Brown, Matthew Wickersham, Franklin Paulino, Hernán F. Peñaloza, Grace Soong, Susan Bueno, Dane Parker, Alice Prince

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


Staphylococcus aureus triggers inflammation through inflammasome activation and recruitment of neutrophils, responses that are critical for pathogen clearance but are associated with substantial tissue damage. We postulated that necroptosis, cell death mediated by the RIPK1/RIPK3/MLKL pathway, would function to limit pathological inflammation. In models of skin infection or sepsis, Mlkl−/− mice had high bacterial loads, an inability to limit interleukin-1b (IL-1b) production, and excessive inflammation. Similarly, mice treated with RIPK1 or RIPK3 inhibitors had increased bacterial loads in a model of sepsis. Ripk3−/− mice exhibited increased staphylococcal clearance and decreased inflammation in skin and systemic infection, due to direct effects of RIPK3 on IL-1b activation and apoptosis. In contrast to Casp1/4−/− mice with defective S. aureus killing, the poor outcomes of Mlkl−/− mice could not be attributed to impaired phagocytic function. We conclude that necroptotic cell death limits the pathological inflammation induced by S. aureus.

Original languageEnglish (US)
Pages (from-to)2219-2230
Number of pages12
JournalCell Reports
Issue number8
StatePublished - Aug 23 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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