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M2 macrophage-derived exosomal-miR-590-3p attenuates DSS-induced mucosal damage and promotes epithelial repair via the LATS1/YAP/β-catenin signalling axis.

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 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 TNF-α, IL-1β, and IL-6. More importantly, repression miR-590-3p in M2-exos resulted with severer 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 (UC).