title: microRNA-146a promotes mycobacterial survival in macrophages through suppressing nitric oxide production.
abstract: Macrophages play a crucial role in host innate anti-mycobacterial defense, which is tightly regulated by multiple factors, including microRNAs. Our previous study showed that a panel of microRNAs was markedly up-regulated in macrophages upon mycobacterial infection. Here, we investigated the biological function of miR-146a during mycobacterial infection. miR-146a expression was induced both in vitro and in vivo after Mycobacterium bovis BCG infection. The inducible miR-146a could suppress the inducible nitric oxide (NO) synthase (iNOS) expression and NO generation, thus promoting mycobacterial survival in macrophages. Inhibition of endogenous miR-146a increased NO production and mycobacterial clearance. Moreover, miR-146a attenuated the activation of nuclear factor κB and mitogen-activated protein kinases signaling pathways during BCG infection, which in turn repressed iNOS expression. Mechanistically, miR-146a directly targeted tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) at post-transcriptional level. Silencing TRAF6 decreased iNOS expression and NO production in BCG-infected macrophages, while overexpression of TRAF6 reversed miR-146a-mediated inhibition of NO production and clearance of mycobacteria. Therefore, we demonstrated a novel role of miR-146a in the modulation of host defense against mycobacterial infection by repressing NO production via targeting TRAF6, which may provide a promising therapeutic target for tuberculosis.
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.|Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Guangzhou Chest Hospital, Guangzhou, 510095, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Sitang
authors.initials: S
authors.lastname: Gong
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Li
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Minhao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lai
authors.affiliation: Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Gucheng
authors.initials: G
authors.lastname: Zeng
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Program of Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.|Institute of Tuberculosis Control, Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions / Q000235:genetics; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D050296:Microbial Viability; D018613:Microscopy, Confocal; D009163:Mycobacterium bovis / Q000254:growth & development* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II