title: MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway.
abstract: A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127-mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti-miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Hangjie
authors.initials: H
authors.lastname: Ying
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Dongjiu
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; and.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China shi_liyun@msn.com xufeng99@yahoo.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China; shi_liyun@msn.com xufeng99@yahoo.com.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D004731:Endotoxins / Q000009:adverse effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008024:Ligands; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D004731:Endotoxins; D008024:Ligands; D035683:MicroRNAs; C533109:Mirn127 microRNA, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D051193:Toll-Like Receptors; D054638:Dual Specificity Phosphatase 1