MicroRNA-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses in inflammatory bowel disease

Abstract

MicroRNA (miR)-219a-5p has been implicated in the development of numerous progression of carcinoma and autoimmune diseases. However, whether miR-219a-5p is involved in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. In this study, we demonstrated that miR-219a-5p expression was significantly decreased in the inflamed intestinal mucosa and peripheral blood (PB)-CD4+ T cells from patients with IBD. Proinflammatory cytokines (e.g., IL-6, IL-12, IL-23 and TNF-α) inhibited miR-219a-5p expression in CD4+ T cells in vitro. Lentivirus-mediated miR-219a-5p downregulation facilitated Th1/Th17 cell differentiation, whereas miR-219a-5p overexpression exerted an opposite effect. Luciferase assays confirmed that ETS variant 5 (ETV5) was a functional target of miR-219a-5p and ETV5 expression was significantly increased in the inflamed intestinal mucosa and PB-CD4+ T cells from IBD patients. ETV5 overexpression enhanced Th1/Th17 immune response through upregulating the phosphorylation of STAT3 and STAT4. Importantly, supplementation of miR-219a-5p ameliorated TNBS-induced intestinal mucosal inflammation, characterized by decreased IFN-γ+ CD4+ T cells and IL-17A+ CD4+ T cells infiltration in the colonic lamina propria. Our data thus reveal a novel mechanism whereby miR-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses. miR-219a-5p might be a target for the treatment of IBD.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81700494), Jiangsu Provincial Key Research and Development Program (BE2017692) and supporting funds from Zhenjiang Municipal Health Commission and Affiliated People’s Hospital of Jiangsu University (K201733, K201741).

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Y.S. conceived the project and wrote the manuscript. Y.X. and J.Y. supervised the experimental work and revised the manuscript; Y.S., C.Q., Y.Z. and T.W. performed the experiments and data analysis. Y.X., C.X., and S.D. diagnosed the patients, recorded the consent and provided clinical samples and information.

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Correspondence to Jun Yao or Yaping Xu.

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Shi, Y., Dai, S., Qiu, C. et al. MicroRNA-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses in inflammatory bowel disease. Mucosal Immunol 13, 303–312 (2020). https://doi.org/10.1038/s41385-019-0216-7

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