IL-33在炎症性肠病肠粘膜屏障损伤修复中的作用及机制研究

Inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis (UC), are characterized by chronic relapsing intestinal diseases that affect the human digestive tract. Furthermore, the perpetual state of inflammation predisposes individuals to the development of colitis-associated cancer. Although evidence implies that genetic susceptibility and environmental triggers accelerate the immunopathogenic process, the etiology of IBD is still unknown. The current studies show that intestinal mucosal barrier dysfunction, which induces increased intestinal epithelial permeability and abnormal immune response to intestinal mucosa, exert an essential role in the development of IBD. . IL-33 is a newly recognized member of the IL-1 family and has been best identified as a potent inducer of Th2-type immune responses. Our recent studies have demonstrated that IL-33 plays a beneficial role in TNBS-induced colitis by switch Th1- to Th2-type immune response and upregulation of Treg cell function, as well as in skin wound model by acceleration of alternatively activated (M2) macrophage development. In addition, several studies reported that transcript levels of IL-33 were enhanced within the affected colon mucosa also during remission when compared with noninvolved colonic areas in patients with both UC and CD. Whether patients in remission also display IL-33 upregulation in affected healed mucosa is yet to be confirmed. In turn, the elevated IL-33 improves the clinical symptoms of intestinal dysfunction caused by IBD.. In the present study, we further explore the potential effect of IL-33 on the repair of intestinal mucosal barrier injury in the animal model of inflammatory bowel diseases. This research will include the relationship of IL-33 and Th1/Th2-cytokines such as INF-γ, IL-4 and IL-13, the influence of IL-33 on the polarization of macrophages into M2 type, as well as the effect of IL-33 on intestinal epithelial permeability. Altogether, through clarifying the effect of IL-33 in both intestinal immune balance and mucosal barrier function stability, this study will provide new insights for prevention and treatment of IBD.

炎症性肠病（IBD）是一类慢性炎症为特征的肠道炎性疾病，其发病率呈上升趋势，且与大肠癌发生密切相关，严重危及人类健康状况。肠黏膜屏障功能障碍引起肠上皮通透性增加，激活肠粘膜异常免疫反应，成为IBD发病的关键环节。申请者前期发现白细胞介素(IL)-33通过上调Th2/Treg细胞功能降低肠黏膜炎症反应，并可诱导M2型巨噬细胞极化促组织损伤后修复。此外，IL-33在肠上皮细胞受抗原刺激或损伤时释放，可改善肠道功能异常所致IBD临床症状。本项目拟建立小鼠IBD疾病模型，深入探讨IL-33在IBD肠粘膜屏障损伤修复中的作用，包括①IL-33与Th1/Th2型细胞因子相互关系；②IL-33对M2型巨噬细胞极化和功能的影响；③IL-33对肠黏膜上皮通透性的影响。本项目通过阐明IL-33在维持肠道免疫平衡与肠道粘膜屏障功能稳定中的双重效应，可望从新的视角揭示IBD发病机制，并为IBD防治提供新的策略。

炎症性肠病（IBD）是一类病因未明的慢性非特异性肠道炎症性疾病, 其发病率呈上升趋势，并伴恶变倾向，已成为影响人类健康的重要威胁。肠黏膜屏障功能障碍引起肠上皮通透性增加，激活肠粘膜异常免疫反应，成为IBD发病的关键环节。本项目通过建立小鼠IBD疾病模型，探讨白细胞介素(IL)-33在维持肠道内环境稳态中的作用及潜在机制。研究发现肠道炎症发生时，出现黏膜组织损伤及炎性细胞浸润，作为警报素的IL-33可经主动（活化的免疫细胞）或被动（损伤的肠上皮细胞）方式释放；外源性IL-33处理能明显改善肠道功能异常所致的IBD病理症状。IL-33上调Th2细胞功能活性，抑制Th1型免疫应答，诱导巨噬细胞向M2型极化，降低肠粘膜炎症反应，促进肠道免疫功能稳定；IL-33直接调节肠上皮细胞紧密连接蛋白生成，或间接诱导肠上皮分泌神经营养因子，经自分泌方式调节肌球蛋白轻链激酶（MLCK）信号通路，影响紧密连接蛋白表达，改善肠上皮屏障通透性；IL-33通过结合肠道干细胞表面特异性受体ST2，调节肠道干细胞增殖，促进肠道类器官的出芽生长，进而改善肠上皮损伤修复。本项目证实IL-33在维持肠道免疫平衡、肠粘膜损伤修复和肠粘膜屏障功能稳定中的多重效应，为阐明IBD的发病机制提供新的思路，并为将IL-33作为IBD防治的新靶点提供科学支持。