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RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome.
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.
Afiliação
  • Zelic M; Department of Molecular, Cell and Cancer Biology, and.
  • Roderick JE; Department of Molecular, Cell and Cancer Biology, and.
  • O'Donnell JA; Department of Molecular, Cell and Cancer Biology, and.
  • Lehman J; Department of Molecular, Cell and Cancer Biology, and.
  • Lim SE; Department of Molecular, Cell and Cancer Biology, and.
  • Janardhan HP; Division of Cardiovascular Medicine and Department of Medicine, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Trivedi CM; Division of Cardiovascular Medicine and Department of Medicine, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Pasparakis M; Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Kelliher MA; Department of Molecular, Cell and Cancer Biology, and.
J Clin Invest ; 128(5): 2064-2075, 2018 05 01.
Article em En | MEDLINE | ID: mdl-29664014
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endotélio Vascular / Síndrome de Resposta Inflamatória Sistêmica / Proteína Serina-Treonina Quinases de Interação com Receptores / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endotélio Vascular / Síndrome de Resposta Inflamatória Sistêmica / Proteína Serina-Treonina Quinases de Interação com Receptores / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article