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Abstract Inflammatory bowel disease (IBD) is a chronic autoimmune disease, and its pathogenesis remains mostly unknown. MicroRNAs (miRs) has drawn much attention as a crucial regulator of autoimmune diseases. In this study, we demonstrated, for the first time, that miR-425 was significantly up-regulated in peripheral blood mononuclear cells (PBMC) and mucosa of patients with IBD. In note, T helper (Th) 17 cells were found to be the major source of miR-425 expression. Using gain-of-function approaches, we demonstrated that miR-425 could facilitate the differentiation of CD4+ T cells into Th17 lineage. In addition, forkhead box O1 (Foxo1) was identified as a novel target gene of miR-425, which was able to inhibit Th17 cell differentiation, and it was observed to be markedly decreased in PBMC and mucosa of patients with IBD. Notably, in vivo inhibition of miR-425 significantly alleviated the disease severity of TNBS-induced colitis in mice, with down-regulated levels of IL-17A. Our data reveal a novel mechanism in which the elevated miR-425 in IBD mediates pathogenic Th17 cell generation through down-regulation of Foxo1. In vivo blockade of miR-425 may serve as a novel therapeutic approach in the treatment of IBD. Highlights • MiR-425 expression is significantly increased in patients with IBD. • MiR-425 promotes pathogenic Th17 cell differentiation. • Foxo1 is a novel target of miR-425. • In vivo inhibition of miR-425 alleviates TNBS-induced colitis in mice. [ABSTRACT FROM AUTHOR]

Abstract Inflammatory bowel disease (IBD) has been well-documented as a chronic gastrointestinal autoimmune disease, but its etiology remains to be elusive. Ascl2 (achaete-scute complex homologue 2), identified as a homologue of the Drosophila achaete-scute gene, has been shown to play an essential for the pathogenesis of autoimmune diseases and cancers. However, whether it is associated with the pathogenesis of IBD remains unclear. Here, we demonstrated that Ascl2 was greatly down-regulated in human IBD and experimental colitis. Interestingly, CD4+ T cell expression of Ascl2 was regulated by intestinal microbiota. Moreover, we revealed that Ascl2 inhibited the differentiation of Th17 cells and restrained their pathogenicity through facilitating IL-10 production. We further showed that Blimp-1 might be involved in the Ascl2-inducing IL-10 expression in CD4+ T cells under Th17 differentiating condition. Notably, lentivirus-mediated overexpression of Ascl2 remarkably alleviated the severity of 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis in mice, with decreased level of colonic IL-17A. Our findings demonstrated an unappreciated mechanism whereby Ascl2 negatively modulates pathogenic Th17 cell differentiation via promoting IL-10 production, and alleviates intestinal inflammation. Thus, Ascl2 may serve as a novel therapeutic target of IBD. Highlights • Ascl2 expression is significantly down-regulated in patients with IBD. • Ascl2 expression is regulated by intestinal microbiota. • Ascl2 suppresses Th17 differentiation and facilitates IL-10 production. • In vivo over expression of Ascl2 alleviates experimental colitis in mice. [ABSTRACT FROM AUTHOR]