ETS translocation variant 5 (ETV5) promotes CD4+ T cell-mediated intestinal inflammation and fibrosis in inflammatory bowel diseases

Caiyun Ma; Yan Shi; Shan Wu; Xin Ye; Qian Zhuang; Min Ning; Jie Xia; Shuang Shen; Zhixia Dong; Dafan Chen; Zhanju Liu; Xinjian Wan

doi:10.1016/j.mucimm.2024.03.010

ETS translocation variant 5 (ETV5) promotes CD4⁺ T cell-mediated intestinal inflammation and fibrosis in inflammatory bowel diseases

Mucosal Immunol. 2024 Mar 28:S1933-0219(24)00030-8. doi: 10.1016/j.mucimm.2024.03.010. Online ahead of print.

Authors

Caiyun Ma¹, Yan Shi², Shan Wu², Xin Ye², Qian Zhuang², Min Ning², Jie Xia², Shuang Shen², Zhixia Dong², Dafan Chen², Zhanju Liu³, Xinjian Wan⁴

Affiliations

¹ Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
² Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: liuzhanju88@126.com.
⁴ Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: slwanxinjian2020@126.com.

PMID: 38555025
DOI: 10.1016/j.mucimm.2024.03.010

Abstract

E26 transformation-specific translocation variant 5 (ETV5) has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the exact roles of ETV5 in regulating CD4⁺ T cell-mediated intestinal inflammation and fibrosis formation remain unclear. Here, we reveal that ETV5 overexpression induced interleukin (IL)-9 and its transcription factor IRF4 expression in IBD CD4⁺ T cells under T helper type 9 (Th9) cells-polarizing conditions. The silencing of IRF4 inhibited ETV5-induced IL-9 expression. CD4⁺ T cell-specific ETV5 deletion ameliorated intestinal inflammation and fibrosis in trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis and CD4⁺ T cell-transferred recombination-activating gene-1 knockout (Rag1^-/-) colitis mice, characterized by less CD4⁺ T cell infiltration and lower fibroblast activation and collagen deposition in the colonic tissues. Furthermore, IL-9 treatment aggressive TNBS-induced intestinal fibrosis in CD4⁺ T cell-specific ETV5 deletion and wild-type control mice. In vitro, human intestinal fibroblasts cocultured with ETV5 overexpressed-Th9 cells expressed higher levels of collagen I and III, whereas an inclusion of anti-IL-9 antibody could reverse this effect. Ribonucleic acid sequencing analysis demonstrated that IL-9 upregulated TAF1 expression in human intestinal fibroblasts. Clinical data showed that number of α-smooth muscle actin⁺TAF1⁺ fibroblasts are higher in inflamed mucosa of patients with IBD. Importantly, TAF1 small interfering ribonucleic acid treatment suppressed IL-9-mediated profibrotic effect in vitro. These findings reveal that CD4⁺ T cell-derived ETV5 promotes intestinal inflammation and fibrosis through upregulating IL-9-mediated intestinal inflammatory and fibrotic response in IBD. Thus, the ETV5/IL-9 signal pathway in T cells might represent a novel therapeutic target for intestinal inflammation and fibrosis in IBD.