@article{d59e34eaddd24292af4b32e4f5ad6641,
title = "Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling",
abstract = "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.",
author = "Kipyegon Kitur and Sarah Wachtel and Armand Brown and Matthew Wickersham and Franklin Paulino and Pe{\~n}aloza, {Hern{\'a}n F.} and Grace Soong and Susan Bueno and Dane Parker and Alice Prince",
note = "Funding Information: Special thanks to John Silke (WEHI) and Douglas R. Green (St. Jude Children{\textquoteright}s Research Hospital) for providing us with Mlkl −/− mice and Vishva Dixit (Genentech) for Ripk3 −/− mice. We are grateful to Scott B. Berger and Peter J. Gough (GlaxoSmithKline) for providing us with GSK3002963. We thank John Silke (WEHI), Douglas R. Green (St. Jude Children{\textquoteright}s Research Hospital), and Razqallah Hakem (UHN, University of Toronto) for providing us with Casp8 −/− Ripk3 −/− mice bone marrows. Research reported in this publication was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, NIH, under award S10RR027050. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by FONDECYT 1140010, Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica, P09-016-F from the Millennium Institute in Immunology and Immunotherapy of the Ministry of Economy of Chile, and Biomedical Research Consortium 13CTI-21526-P5 from INNOVA-CORFO Chile to S.B. and NIH grants 5R01HL079395 and 5R01AI103854 to A.P. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = aug,
day = "23",
doi = "10.1016/j.celrep.2016.07.039",
language = "English (US)",
volume = "16",
pages = "2219--2230",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}