M2 Macrophage-Derived Exosomal miR-590-3p Attenuates DSS-Induced Mucosal Damage and Promotes Epithelial Repair via the LATS1/YAP/ β-Catenin Signalling Axis. (19th October 2020)

• Record Type: Journal Article
• Authors: Deng, Feihong; Yan, Jin; Lu, Jiaxi; Luo, Min; Xia, Pianpian; Liu, Siliang; Wang, Xuehong; Zhi, Fachao; Liu, Deliang
• Is Part Of: Journal of Crohn's and colitis. Volume 15:Number 4(2021)
• Page Start: 665
• Page End: 677
• Publication Date: 2020-10-19
• Subjects: Exosomes -- M2 macrophages -- miR-590-3p -- YAP/β-catenin signalling -- epithelial regeneration; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjaa214
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: M2 phenotype macrophages are involved in the resolution of inflammation and intestinal repair. Exosomes are emerging as important mediators of intercellular communication in the mucosal microenvironment. Methods: M2 macrophages were transfected with or without miR-590-3p. Exosomes derived from M2 macrophages were isolated and identified. Proliferation and wound healing were tested in vitro and compared between groups. The mechanism involving LATS1, and activation of YAP and β-catenin signalling was investigated by using plasmid transfection, western blotting, immunofluorescence and luciferase reporter assays. The effect of exosomes in vivo was detected in dextran saline sulphate [DSS]-induced murine colitis. Results: First, we demonstrated that M2 macrophages promoted colonic epithelial cell proliferation in an exosome-dependent manner. Epithelial YAP mediated the effect of M2 macrophage-derived exosomes [M2-exos] in epithelial proliferation. Moreover, miR-590-3p, which was significantly enriched in M2-exos, could be transferred from macrophages into epithelial cells, resulting in the enhanced proliferation and wound healing of epithelial cells. Mechanistically, miR-590-3p suppressed the expression of LATS1 by binding to its coding sequence and subsequently activated the YAP/β-catenin-modulated transcription process to improve epithelial cell wound-healing ability. miR-590-3p also inhibited the induction of pro-inflammatory cytokines, including tumour necrosis factor-α, interleukin-1β [IL-1β] and IL-6. More importantly, repression of miR-590-3p in M2-exos resulted in more severe mucosal damage and impaired colon repair of mice compared with those in M2-exo-treated mice after DSS-induced colitis. Conclusion: M2 macrophage-derived exosomal miR-590-3p reduces inflammatory signals and promotes epithelial regeneration by targeting LATS1 and subsequently activating YAP/β-catenin-regulated transcription, which could offer a new opportunity for clinical therapy for ulcerative colitis.