miR-146a mediates protective innate immune tolerance in the neonate intestine.
After birth, the intestinal mucosa undergoes a dramatic transition from a sterile protected site to an environmentally exposed and permanently colonized surface. The mechanisms that facilitate this transition are ill defined. Here, we demonstrate that microRNA-146a-mediated translational repression and proteolytic degradation of the essential Toll-like receptor (TLR) signaling molecule interleukin 1 receptor associated kinase 1 (IRAK1) is sufficient to induce intestinal epithelial innate immune tolerance and provide protection from bacteria-induced epithelial damage in neonates. Despite low IRAK1 protein levels, continuous TLR4- and IRAK1-dependent signal transduction induced by intraepithelial endotoxin persistence during the neonatal period maintains tolerance through sustained miR-146a expression. Strikingly, it additionally facilitates transcription of a distinct set of genes involved in cell survival, differentiation, and homeostasis. Thus, our results identify the underlying molecular mechanisms of intestinal epithelial innate immune tolerance during the neonatal period and characterize tolerance as an active condition involved in the establishment of intestinal mucosal homeostasis.
Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany.
Cécilia
C
Chassin
Magdalena
M
Kocur
Johanna
J
Pott
Claudia U
CU
Duerr
Dominique
D
Gütle
Michael
M
Lotz
Mathias W
MW
Hornef
D000818:Animals; D002460:Cell Line; D004731:Endotoxins / Q000276:immunology; D004927:Escherichia coli Infections / Q000378:metabolism; D007108:Immune Tolerance; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology
D004731:Endotoxins; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse