Cell Host & Microbe
Volume 8, Issue 4, 21 October 2010, Pages 358-368
Journal home page for Cell Host & Microbe

Article
miR-146a Mediates Protective Innate Immune Tolerance in the Neonate Intestine

https://doi.org/10.1016/j.chom.2010.09.005Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► IRAK1 downregulation induces intestinal tolerance and protects neonates from bacterial damage ► miR-146a and proteolytic degradation mediate IRAK1 downregulation ► Endotoxin persistence drives continuous TLR4 signaling and expression of miR-146a ► TLR signaling also induces a distinct set of genes for establishing mucosal homeostasis

Cited by (0)

2

Present address: Institute of Medical Microbiology and Hygiene, Heinrich-Heine University, 40225 Duesseldorf, Germany

3

Present address: Roche Diagnostics, 68305 Mannheim, Germany