VEGF-C/VEGFR-3信号调控调节性T细胞（Treg）和炎症性肠病（IBD）的新机制

Inflammatory Bowel Diseases (IBD) is a typical chronic inflammation-related gastrointestinal disease, which could be triggered by multiple types of infections. It has been well defined that Foxp3+CD4+ regulatory T cells (Tregs) play critical role to protect from IBD. Recent studies have revealed that intestinal commensal bacteria may provide an important stimulus for local development of Tregs. Our study has identified that the expression of vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3, was upregulated on macrophages upon bacterial infection. Upon binding to VEGF-C, VEGFR-3 restrains acute inflammatory responses mediated by macrophage and protects from bacterial infection-triggered sepsis. Importantly, our preliminary data showed that the expression levels of VEGFR-3 were enhanced on Tregs. When mice carried the tyrosine kinase mutant VEGFR-3 (i.e. Vegfr3TKmut), the induction of Tregs was dampened in response to bacterial infection in vivio. We will further investigate whether VEGF-C concentrations are enhanced in intestine of IBD mice and how VEGFR-3 regulates the development or suppressive function of Tregs to influence the pathogenesis of IBD. To achieve this aim, we have set up DSS-induced colitis mouse models. We will induce colitis using the VEGFR-3 ligand-binding deletion mutant mouse models that were cross-bred with Foxp3-Cre mice in order to specific express VEGFR-3ΔLBD in Tregs. Also Tregs isolated from the Vegfr3TKmut mice will be injected into Rag KO recipient mice intraperitoneally to check how it affects the pathogenesis of IBD. We will explore the possibility and efficacy of ex vivo induction of Tregs with exogenous VEGF-C156S (i.e. the VEGFR-3 agonist) and in vivo VEGF-C156S therapy to treat IBD, which might provide new therapeutic strategy for IBD.

炎症性肠病（IBD）是主要累及胃肠道的慢性炎症相关疾病。肠道益生菌可调控调节性T细胞（Treg）的分化和抑制功能，降低IBD的发生。我们预实验显示Treg细胞升高血管内皮生长因子受体3(VEGFR-3)的表达。VEGFR-3突变后，下调肠道细菌感染诱导的Treg比例。拟探讨IBD病变是否促进肠道分泌更多VEGF-C，激活VEGFR-3信号通路，诱导并增强Treg抑制功能，进而调控IBD的病理进程。拟使用特异性在Treg细胞中表达VEGFR-3ΔLBD（缺失配体结合区）的小鼠，或腹腔注射表达VEGFR-3TKmut（丧失激酶活性）的Treg细胞，结合DSS诱导IBD模型，鉴定VEGFR-3信号通路影响肠道Treg分化和功能的新机制。利用VEGFR受体激动剂VEGF-C156S探索体外扩增Treg细胞或体内抑制IBD发生发展的可行性，为治疗IBD提供新的策略。

炎症性肠病/IBD有大量调节性T细胞、巨噬细胞等的浸润，参与炎症反应和IBD病理过程。申请书拟研究VEGFR-3信号调控Treg的分化或功能，参与IBD发生发展的机制。鉴于VEGFR-3突变小鼠淋巴循环障碍，未能获得充足小鼠执行计划。为避免延误，本课题发现另一种靶分子YAP在IBD浸润巨噬细胞中的表达量受微环境不同细胞因子的调控，并利用在巨噬细胞中特异性敲除YAP的小鼠模型，鉴定YAP促进M1，抑制M2巨噬细胞分化及其加重IBD的机制。这与前人报道YAP促进肠道干细胞增殖和肠上皮修复，降低IBD的功能不同。因此本项目提示应充分考虑YAP在不同细胞类型中的作用，为其作为靶点治疗IBD提供重要信息。