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.
authors.affiliation: Department of Pharmacology, Columbia University, New York, NY 10032, USA.
authors.forename: Kipyegon
authors.initials: K
authors.lastname: Kitur
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wachtel
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Armand
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wickersham
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Franklin
authors.initials: F
authors.lastname: Paulino
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Hernán F
authors.initials: HF
authors.lastname: Peñaloza
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Soong
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Susan
authors.initials: S
authors.lastname: Bueno
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.affiliation: Department of Pharmacology, Columbia University, New York, NY 10032, USA; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: asp7@columbia.edu.
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D058491:Bacterial Load; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology*; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D016019:Survival Analysis
chemical_list: C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1