Format

Send to

Choose Destination
Cell Rep. 2016 Aug 23;16(8):2219-2230. doi: 10.1016/j.celrep.2016.07.039. Epub 2016 Aug 11.

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling.

Author information

1
Department of Pharmacology, Columbia University, New York, NY 10032, USA.
2
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
3
Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
4
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.

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.

PMID:
27524612
PMCID:
PMC5001919
DOI:
10.1016/j.celrep.2016.07.039
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center