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MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury

Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms h...

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Autores principales: Chassin, Cécilia, Hempel, Cordelia, Stockinger, Silvia, Dupont, Aline, Kübler, Joachim F, Wedemeyer, Jochen, Vandewalle, Alain, Hornef, Mathias W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531605/
https://www.ncbi.nlm.nih.gov/pubmed/23143987
http://dx.doi.org/10.1002/emmm.201201298
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author Chassin, Cécilia
Hempel, Cordelia
Stockinger, Silvia
Dupont, Aline
Kübler, Joachim F
Wedemeyer, Jochen
Vandewalle, Alain
Hornef, Mathias W
author_facet Chassin, Cécilia
Hempel, Cordelia
Stockinger, Silvia
Dupont, Aline
Kübler, Joachim F
Wedemeyer, Jochen
Vandewalle, Alain
Hornef, Mathias W
author_sort Chassin, Cécilia
collection PubMed
description Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms have not been fully resolved. Here, we identify post-transcriptional upregulation of the essential Tlr signalling molecule interleukin 1 receptor-associated kinase (Irak) 1 as the causative mechanism for post-ischemic immune hyper-responsiveness of intestinal epithelial cells. Increased Irak1 protein levels enhanced epithelial ligand responsiveness, chemokine secretion, apoptosis and mucosal barrier disruption in an experimental intestinal I/R model using wild-type, Irak1(−/−) and Tlr4(−/−) mice and ischemic human intestinal tissue. Irak1 accumulation under hypoxic conditions was associated with reduced K48 ubiquitination and enhanced Senp1-mediated deSUMOylation of Irak1. Importantly, administration of microRNA (miR)-146a or induction of miR-146a by the phytochemical diindolylmethane controlled Irak1 upregulation and prevented immune hyper-responsiveness in mouse and human tissue. These findings indicate that Irak1 accumulation triggers I/R-induced epithelial immune hyper-responsiveness and suggest that the induction of miR-146a offers a promising strategy to prevent I/R tissue injury.
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spelling pubmed-35316052013-01-04 MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury Chassin, Cécilia Hempel, Cordelia Stockinger, Silvia Dupont, Aline Kübler, Joachim F Wedemeyer, Jochen Vandewalle, Alain Hornef, Mathias W EMBO Mol Med Research Articles Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms have not been fully resolved. Here, we identify post-transcriptional upregulation of the essential Tlr signalling molecule interleukin 1 receptor-associated kinase (Irak) 1 as the causative mechanism for post-ischemic immune hyper-responsiveness of intestinal epithelial cells. Increased Irak1 protein levels enhanced epithelial ligand responsiveness, chemokine secretion, apoptosis and mucosal barrier disruption in an experimental intestinal I/R model using wild-type, Irak1(−/−) and Tlr4(−/−) mice and ischemic human intestinal tissue. Irak1 accumulation under hypoxic conditions was associated with reduced K48 ubiquitination and enhanced Senp1-mediated deSUMOylation of Irak1. Importantly, administration of microRNA (miR)-146a or induction of miR-146a by the phytochemical diindolylmethane controlled Irak1 upregulation and prevented immune hyper-responsiveness in mouse and human tissue. These findings indicate that Irak1 accumulation triggers I/R-induced epithelial immune hyper-responsiveness and suggest that the induction of miR-146a offers a promising strategy to prevent I/R tissue injury. WILEY-VCH Verlag 2012-12 2012-11-09 /pmc/articles/PMC3531605/ /pubmed/23143987 http://dx.doi.org/10.1002/emmm.201201298 Text en Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Research Articles
Chassin, Cécilia
Hempel, Cordelia
Stockinger, Silvia
Dupont, Aline
Kübler, Joachim F
Wedemeyer, Jochen
Vandewalle, Alain
Hornef, Mathias W
MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title_full MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title_fullStr MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title_full_unstemmed MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title_short MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
title_sort microrna-146a-mediated downregulation of irak1 protects mouse and human small intestine against ischemia/reperfusion injury
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531605/
https://www.ncbi.nlm.nih.gov/pubmed/23143987
http://dx.doi.org/10.1002/emmm.201201298
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