MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits

Nat Commun. 2014 Apr 10;5:3619. doi: 10.1038/ncomms4619.

Abstract

MicroRNAs (miRNAs) have been implicated in a spectrum of physiological and pathological conditions, including immune responses. miR-302b has been implicated in stem cell differentiation but its role in immunity remains unknown. Here we show that miR-302b is induced by Toll-like receptor 2 (TLR2) and TLR4 through ERK-p38-NF-κB signalling upon Gram-negative bacterium Pseudomonas aeruginosa infection. Suppression of inflammatory responses to bacterial infection is mediated by targeting IRAK4, a protein required for the activation and nuclear translocation of NF-κB. Through negative feedback, enforced expression of miR-302b or IRAK4 siRNA silencing inhibits downstream NF-κB signalling and airway leukocyte infiltration, thereby alleviating lung injury and increasing survival in P. aeruginosa-infected mice. In contrast, miR-302b inhibitors exacerbate inflammatory responses and decrease survival in P. aeruginosa-infected mice and lung cells. These findings reveal that miR-302b is a novel inflammatory regulator of NF-κB activation in respiratory bacterial infections by providing negative feedback to TLRs-mediated immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Dactinomycin / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microscopy, Confocal
  • Pseudomonas aeruginosa / immunology*
  • RNA, Small Interfering / genetics
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*

Substances

  • MicroRNAs
  • RNA, Small Interfering
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Dactinomycin
  • Interleukin-1 Receptor-Associated Kinases
  • Irak4 protein, mouse