Open AccessMicroRNA‐146a‐mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
Author(s) -
Chassin Cécilia,
Hempel Cordelia,
Stockinger Silvia,
Dupont Aline,
Kübler Joachim F.,
Wedemeyer Jochen,
Vandewalle Alain,
Hornef Mathias W.
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201298
Subject(s) - medical school , epidemiology , medicine , library science , medical education , computer science
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.