RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome
Authors
Zelic, MatijaRoderick, 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 ImmunityDepartment of Medicine, Division of Cardiovascular Medicine
Department of Molecular, Cell and Cancer Biology
Document Type
Journal ArticlePublication Date
2018-05-01Keywords
CoagulationCytokines
Immunology
Inflammation
endothelial cells
Cell Biology
Cells
Immunology and Infectious Disease
Medical Immunology
Pathological Conditions, Signs and Symptoms
Metadata
Show full item recordAbstract
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/JCI96147Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40623PubMed ID
29664014Related Resources
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