Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai, 201299, China.
J Autoimmun. 2022 Oct;132:102872. doi: 10.1016/j.jaut.2022.102872. Epub 2022 Aug 1.
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.
ETS-1 expression was examined in IBD patients. CD45RBCD4 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.
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-1CD45RBCD4 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.
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.
作为人类炎症性肠病（IBD）的易感基因，禽红细胞生成病毒 E26 癌基因同源物-1（ETS-1）如何调节肠道黏膜免疫反应尚不清楚。本研究旨在探讨 ETS-1 在 IBD 发病机制中的潜在作用。
检测 IBD 患者中 ETS-1 的表达。构建 ETS-1 转基因（Tg）小鼠 CD45RBCD4 T 细胞转移结肠炎、葡聚糖硫酸钠（DSS）诱导结肠炎和偶氮甲烷（AOM）/DSS 诱导结肠炎相关癌症（CAC）模型，以探究 ETS-1 在体内的功能。对 Ets-1 Tg 小鼠 CD4 T 细胞进行 RNA 测序，以解析关键差异表达基因。通过腺病毒转导验证 ETS-1 在体内的治疗潜力。
与健康对照相比，活动期 IBD 患者 CD4 T 细胞中 ETS-1 的表达显著增加，TNF-α可上调其表达，而抗 TNF-α mAb 治疗可显著抑制其表达。与对照组相比， Rag1 小鼠重建的 Ets-1CD45RBCD4 T 细胞或 DSS 暴露后的 Ets-1 Tg 小鼠出现更严重的结肠炎，表现为炎症结肠中 TNF-α和 IFN-γ表达更高。Ets-1 Tg 小鼠更易发生 AOM/DSS 诱导的 CAC，骨髓嵌合体进一步证实固有层免疫细胞而非肠道上皮细胞有助于结肠炎的发生。RNA 测序和荧光素酶分析显示冷诱导 RNA 结合蛋白（CIRBP）是 ETS-1 的功能靶点，可促进 Th1 细胞驱动的免疫反应。一致地，腹腔内给予腺病毒-m-cirbp-shRNA 可改善 Ets-1 Tg 小鼠的三硝基苯磺酸（TNBS）诱导结肠炎。
本研究数据表明，ETS-1 在 IBD 患者中高表达，并通过 CIRBP 促进 Th1 驱动的黏膜炎症。CIRBP 可能成为治疗人类 IBD 的新治疗靶点。
