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

Cell Host Microbe. 2010 Oct 21;8(4):358-68. doi: 10.1016/j.chom.2010.09.005.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Endotoxins / immunology
  • Escherichia coli Infections / metabolism
  • Immune Tolerance*
  • Immunity, Innate*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / microbiology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / immunology*
  • MicroRNAs / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / immunology

Substances

  • Endotoxins
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse

Associated data

  • GEO/GSE23755