Department of Molecular, Cell and Cancer Biology; Department of Medicine, Division of Cardiovascular Medicine; Program in Innate Immunity
Cell Biology | Cells | Immunology and Infectious Disease | Medical Immunology | Pathological Conditions, Signs and Symptoms
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.
Coagulation, Cytokines, Immunology, Inflammation, endothelial cells
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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.
DOI of Published Version
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
The Journal of clinical investigation
Zelic, Matija; Roderick, Justine E.; O'Donnell, Joanne A.; Lehman, Jesse; Lim, Sung Eun; Janardhan, Harish P.; Trivedi, Chinmay M.; Pasparakis, Manolis; and Kelliher, Michelle A., "RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome" (2018). Open Access Articles. 3428.