Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-08-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716309573 |
| _version_ | 1819075283232227328 |
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| author | Kipyegon Kitur Sarah Wachtel Armand Brown Matthew Wickersham Franklin Paulino Hernán F. Peñaloza Grace Soong Susan Bueno Dane Parker Alice Prince |
| author_facet | Kipyegon Kitur Sarah Wachtel Armand Brown Matthew Wickersham Franklin Paulino Hernán F. Peñaloza Grace Soong Susan Bueno Dane Parker Alice Prince |
| author_sort | Kipyegon Kitur |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T18:22:57Z |
| format | Article |
| id | doaj.art-6826f89d91474684a9cc047c09ba3385 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T18:22:57Z |
| publishDate | 2016-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6826f89d91474684a9cc047c09ba33852022-12-21T18:54:29ZengElsevierCell Reports2211-12472016-08-011682219223010.1016/j.celrep.2016.07.039Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory SignalingKipyegon Kitur0Sarah Wachtel1Armand Brown2Matthew Wickersham3Franklin Paulino4Hernán F. Peñaloza5Grace Soong6Susan Bueno7Dane Parker8Alice Prince9Department of Pharmacology, Columbia University, New York, NY 10032, USADepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USAMillennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileDepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USAMillennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileDepartment of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Pharmacology, Columbia University, New York, NY 10032, USAStaphylococcus 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.http://www.sciencedirect.com/science/article/pii/S2211124716309573 |
| spellingShingle | Kipyegon Kitur Sarah Wachtel Armand Brown Matthew Wickersham Franklin Paulino Hernán F. Peñaloza Grace Soong Susan Bueno Dane Parker Alice Prince Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling Cell Reports |
| title | Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling |
| title_full | Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling |
| title_fullStr | Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling |
| title_full_unstemmed | Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling |
| title_short | Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling |
| title_sort | necroptosis promotes staphylococcus aureus clearance by inhibiting excessive inflammatory signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716309573 |
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