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.
摘要：
ETS易位变体5（ETV5）与炎症性肠病（IBD）的发病机理有关。然而,ETV5在调节CD4+T细胞介导的肠道炎症和纤维化形成中的确切作用尚不清楚.这里,我们揭示了在Th9极化条件下，ETV5过表达诱导了初始IBDCD4T细胞中IL-9及其转录因子IRF4的表达。IRF4的沉默抑制ETV5诱导的IL-9表达。CD4+T细胞特异性ETV5缺失（CKO）改善了TNBS诱导的实验性结肠炎和CD4+T细胞转移的Rag1-/-结肠炎小鼠的肠道炎症和纤维化，以CD4+T细胞浸润较少为特征，结肠组织中的成纤维细胞活化和胶原沉积降低。此外，IL-9治疗CKO和野生型(WT)对照小鼠中侵袭性TNBS诱导的肠纤维化。体外，与ETV5过表达的Th9细胞共培养的人肠成纤维细胞表达更高水平的胶原蛋白I和III，而包含抗IL-9抗体可以逆转这种作用。RNA测序分析表明，IL-9上调了人肠成纤维细胞中TAF1的表达。临床数据显示，IBD患者炎症粘膜中α-SMATAF1成纤维细胞的数量较高。重要的是,TAF1siRNA处理在体外抑制IL-9介导的促纤维化作用。这些发现揭示了CD4+T细胞来源的ETV5通过上调IL-9介导的肠道炎症和纤维化反应促进肠道炎症和纤维化。因此，T细胞中的ETV5/IL-9信号通路可能是IBD肠道炎症和纤维化的新治疗靶点。
