ETS-1 facilitates Th1 cell-mediated mucosal inflammation in inflammatory bowel diseases through upregulating CIRBP

Abstract

Background & aims: As a susceptibility gene for human inflammatory bowel diseases (IBD), how avian erythroblastosis virus E26 oncogene homolog-1 (ETS-1) modulates intestinal mucosal immune response remains unclear. Here we studied the potential roles of ETS-1 in the pathogenesis of IBD.

Methods: ETS-1 expression was examined in IBD patients. CD45RB^highCD4⁺ T cell-transfer colitis, dextran sulfate sodium (DSS)-induced colitis, and azomethane (AOM)/DSS-induced colitis-associated cancer (CAC) models were constructed to probe the function of ETS-1 in vivo. RNA-sequencing of CD4⁺ T cells from Ets-1 transgenic (Tg) mice was performed to decipher the key differentially expressed genes. Adenovirus transduction was conducted to verify the therapeutic potentials of ETS-1 in vivo.

Results: ETS-1 expression was significantly increased in CD4⁺ T cells from active IBD patients compared with healthy controls, which was upregulated by TNF-α but markedly suppressed by anti-TNF-α mAb therapy. More severe colitis was observed in Rag1^-/- mice reconstituted with Ets-1^TgCD45RB^highCD4⁺ T cells or in Ets-1 Tg mice after DSS exposure compared with controls, characterized by higher TNF-α and IFN-γ expression in inflamed colon. Ets-1 Tg mice were more prone to develop AOM/DSS-induced CAC, and bone marrow chimeras further proved that lamina propria immune cells but not intestinal epithelial cells contributed to the development of colitis. RNA-sequencing and luciferase analysis revealed cold-inducible RNA-binding protein (CIRBP) as a functional target of ETS-1 to promote Th1 cell-driven immune response. Consistently, intraperitoneal administration of adenovirus-m-cirbp-shRNA ameliorated trinitrobenzene sulfonic acid (TNBS)-induced colitis of Ets-1 Tg mice.

Conclusions: Our data identify that ETS-1 is highly expressed in IBD patients and promotes Th1-driven mucosal inflammation through CIRBP. CIRBP may serve as a novel therapeutic target for treatment of human IBD.

Keywords: CIRBP; Colitis; ETS-1; Inflammatory bowel diseases; Th1 immune response.