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

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.

• Authors: Xikun Zhou, Xuefeng Li, Yan Ye, Kelei Zhao, Yan Zhuang, Yi Li, Yuquan Wei, Min Wu
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 3619 (Apr 10 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 24717937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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