Universität zu Köln

Zelic, Matija, Roderick, Justine E., O'Donnell, Joanne A., Lehman, Jesse, Lim, Sung Eun, Janardhan, Harish P., Trivedi, Chinmay M., Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kelliher, Michelle A. (2018). RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J. Clin. Invest., 128 (5). S. 2064 - 2076. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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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 Ripk1(D138N/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 Ripk1(D138N/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 Ripk1(D138N/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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Roderick, Justine E. UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Donnell, Joanne A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehman, Jesse UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Sung Eun UNSPECIFIED UNSPECIFIED UNSPECIFIED Janardhan, Harish P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trivedi, Chinmay M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kelliher, Michelle A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-188058
DOI:	10.1172/JCI96147
Journal or Publication Title:	J. Clin. Invest.
Volume:	128
Number:	5
Page Range:	S. 2064 - 2076
Date:	2018
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TUMOR-NECROSIS-FACTOR; SEVERE SEPSIS; SEPTIC SHOCK; DOUBLE-BLIND; CELL-DEATH; PROGRAMMED NECROSIS; PHASE-III; TNF-ALPHA; IN-VIVO; MLKL Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18805