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.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Apoptosis / immunology*
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Bacterial Load
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspases / genetics
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Caspases / immunology
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Caspases, Initiator
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Cell Line
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Gene Expression Regulation
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HEK293 Cells
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Humans
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Inflammasomes / genetics
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Inflammasomes / immunology
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Keratinocytes
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Necrosis / immunology*
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Kinases / immunology*
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / immunology
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Sepsis / genetics
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Sepsis / immunology*
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Sepsis / mortality
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Sepsis / pathology
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Signal Transduction
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Staphylococcal Infections / genetics
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Staphylococcal Infections / immunology*
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Staphylococcal Infections / pathology
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Staphylococcal Skin Infections / genetics
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Staphylococcal Skin Infections / immunology*
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Staphylococcal Skin Infections / pathology
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Staphylococcus aureus / growth & development
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Staphylococcus aureus / immunology*
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Staphylococcus aureus / pathogenicity
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Survival Analysis
Substances
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IL1B protein, mouse
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Inflammasomes
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Interleukin-1beta
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MLKL protein, mouse
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Protein Kinases
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk1 protein, mouse
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Ripk3 protein, mouse
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Casp4 protein, mouse
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Caspases
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Caspases, Initiator
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Caspase 1