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

• DOI: 10.1038/ncomms4619
• Publication Date: 2014-04-10T11:40:12Z
• Authors: Xikun Zhou; Xuefeng Li; Yan Ye; Kelei Zhao; Yan Zhuang; Yi Li; Yuquan Wei; Min Wu
• Keywords: Mice, Knockout; 0301 basic medicine; Microscopy, Confocal; Blotting, Western; Article; Toll-Like Receptor 2; 3. Good health; Mice, Inbred C57BL; Toll-Like Receptor 4; Mice; MicroRNAs; 03 medical and health sciences; Interleukin-1 Receptor-Associated Kinases; Gene Expression Regulation; Pseudomonas aeruginosa; Dactinomycin; Animals; Female; RNA, Small Interfering; Cells, Cultured

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.