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    RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome

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    Authors
    Zelic, Matija
    Roderick, Justine E.
    O'Donnell, Joanne A.
    Lehman, Jesse
    Lim, Sung Eun
    Janardhan, Harish P.
    Trivedi, Chinmay M.
    Pasparakis, Manolis
    Kelliher, Michelle A.
    UMass Chan Affiliations
    Program in Innate Immunity
    Department of Medicine, Division of Cardiovascular Medicine
    Department of Molecular, Cell and Cancer Biology
    Document Type
    Journal Article
    Publication Date
    2018-05-01
    Keywords
    Coagulation
    Cytokines
    Immunology
    Inflammation
    endothelial cells
    Cell Biology
    Cells
    Immunology and Infectious Disease
    Medical Immunology
    Pathological Conditions, Signs and Symptoms
    
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    Abstract
    Receptor interacting protein kinase 1 (RIPK1) has important kinase-dependent and kinase-independent scaffolding functions that activate or prevent apoptosis or necroptosis in a cell context-dependent manner. The kinase activity of RIPK1 mediates hypothermia and lethality in a mouse model of TNF-induced shock, reflecting the hyperinflammatory state of systemic inflammatory response syndrome (SIRS), where the proinflammatory "cytokine storm" has long been viewed as detrimental. Here, we demonstrate that cytokine and chemokine levels did not predict survival and, importantly, that kinase-inactive Ripk1D138N/D138N hematopoietic cells afforded little protection from TNF- or TNF/zVAD-induced shock in reconstituted mice. Unexpectedly, RIPK1 kinase-inactive mice transplanted with WT hematopoietic cells remained resistant to TNF-induced shock, revealing that a nonhematopoietic lineage mediated protection. TNF-treated Ripk1D138N/D138N mice exhibited no significant increases in intestinal or vascular permeability, nor did they activate the clotting cascade. We show that TNF administration damaged the liver vascular endothelium and induced phosphorylated mixed lineage kinase domain-like (phospho-MLKL) reactivity in endothelial cells isolated from TNF/zVAD-treated WT, but not Ripk1D138N/D138N, mice. These data reveal that the tissue damage present in this SIRS model is reflected, in part, by breaks in the vasculature due to endothelial cell necroptosis and thereby predict that RIPK1 kinase inhibitors may provide clinical benefit to shock and/or sepsis patients.
    Source

    J Clin Invest. 2018 May 1;128(5):2064-2075. doi: 10.1172/JCI96147. Epub 2018 Apr 16. Link to article on publisher's site

    DOI
    10.1172/JCI96147
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/40623
    PubMed ID
    29664014
    Related Resources

    Link to Article in PubMed

    Rights
    Copyright © 2018, American Society for Clinical Investigation. Publisher pdf posted as allowed by the publisher's open access policy at https://jci.org/kiosks/terms.
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI96147
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