MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits.
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.
1] Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA [2] State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3].
Xikun
X
Zhou
1] Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA [2] State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3].
Xuefeng
X
Li
Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.
Yan
Y
Ye
Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.
Kelei
K
Zhao
Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.
Yan
Y
Zhuang
1] Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA [2] State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Yi
Y
Li
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Yuquan
Y
Wei
Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.
Min
M
Wu
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D003609:Dactinomycin; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse