title: Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells.
abstract: MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1(-/-) mice showed that CD4(+)CD25(+) regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10-secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPβ, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.
authors.affiliation: Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Guo
authors.forename: Zhenke
authors.initials: Z
authors.lastname: Wen
authors.forename: Andong
authors.initials: A
authors.lastname: Qin
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Liao
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Liang
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D016753:Interleukin-10 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000008:administration & dosage* / Q000627:therapeutic use; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000627:therapeutic use; D020127:Recovery of Function / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016376:Oligonucleotides, Antisense; D016753:Interleukin-10