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
Affiliations
Kipyegon Kitur
Department of Pharmacology, Columbia University, New York, NY 10032, USA
Sarah Wachtel
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Armand Brown
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Matthew Wickersham
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Franklin Paulino
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Hernán F. Peñaloza
Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
Grace Soong
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Susan Bueno
Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
Dane Parker
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Alice Prince
Department of Pharmacology, Columbia University, New York, NY 10032, USA
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.
