title: MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury.
abstract: 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.
authors.affiliation: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. cecilia.chassin@gmail.com
authors.forename: Cécilia
authors.initials: C
authors.lastname: Chassin
authors.forename: Cordelia
authors.initials: C
authors.lastname: Hempel
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.forename: Aline
authors.initials: A
authors.lastname: Dupont
authors.forename: Joachim F
authors.initials: JF
authors.lastname: Kübler
authors.forename: Jochen
authors.initials: J
authors.lastname: Wedemeyer
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D000818:Animals; D015536:Down-Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000098:blood supply / Q000276:immunology / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D015398:Signal Transduction
chemical_list: C554180:MIRN146 microRNA, rat; D035683:MicroRNAs; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases