外周免疫失衡与炎症性自身免疫病相关疾病发生发展的细胞分子机制

Proper control of mucosal immunity and inflammation is essential for the health of intestine while its disruption is known to be associated with the initiation and progression of autoimmune diseases and cancer. Therefore, elucidation of the local immune-regulatory mechanisms under either pathological or physiological condition controlled by different mucosal cell types will provide new strategies for the prevention and treatment of related diseases. We have previously reported the critical roles of MEKK2 and MEKK3 in the regulation of the MAPK signaling pathways. We show that interruption of the MEKK2/3-mediated MAPK signal leads to aberrant T cell differentiation and functionality, resulting in susceptibility to autoimmune diseases such as EAE and IBD. In this proposal, we will use our MEKK2 and/or MEKK3 targeting mice, to investigate the roles of MEKK2 or MEKK3 in regulating the immune homeostasis or chestrated by immune cells and epithelial cells in intestine using colitis and colitis-related tumor models. Their clinical relevance to Crohn’s diseases and colon cancer will also be studied using human patient samples. Our study may unravel novel drug targets in the MEKK2/3 signaling pathways for future applications in clinic.

肠道粘膜局部免疫应答格局和调控机制异常导致的免疫失衡与多种免疫性疾病及肿瘤发生密切相关。深入阐明肠道局部多种细胞参与下的免疫应答分子机制不仅有利于解析肠道局部多细胞间的相互作用，更可为探索疾病治疗提供新策略。申请人已对MAPK信号通路重要分子MEKK2和MEKK3在Th细胞分化和免疫应答方面开展系列研究，发现其与自身免疫性疾病的发生发展密切相关。据此提出“MEKK家族分子参与的MAPK信号通路在调节肠道局部免疫应答格局和病理性炎症中的作用机制”的关键科学问题。利用小鼠模型和临床样本，围绕肠道局部T淋巴细胞和肠上皮细胞，本课题将深入探索MEKK2/3缺失造成的MAPK信号通路异常影响肠道局部免疫失衡及炎症性自身免疫病及相关肠道肿瘤发生发展中的作用机制，为深入解析肠道局部免疫失衡的细胞分子机制提供新的理论依据，同时也为基于该信号通路的免疫调节剂在肠道疾病中的潜在新靶点选择和应用奠定基础。

肠道是重要的区域免疫器官，多种肠道细胞及肠道微环境协同维持肠道免疫稳态，稳态失衡导致炎性肠病（IBD）等肠道疾病乃至全身性疾病。肠道免疫稳态的形成机制目前仍不甚清楚。本项目通过对肠道T细胞在IBD过程中的研究，发现由MEKK2调控的信号通路通过感知炎症因子信号，增强促炎Th1在肠道分化，恶化IBD进展。除T细胞之外本项目还发现MEKK2也通过肠道间质细胞调节肠道免疫稳态与IBD进展，并在机制上阐明了肠道间质细胞通过Mekk2-ERK5通路响应ROS刺激，进而激活KLF2促进Rspo1表达，由此促进上皮修复与肠炎缓解。本研究揭示了维持肠道干细胞稳态的细胞和分子机制并发现了多个关键间质细胞亚群，为IBD等相关疾病的治疗提供潜在的新靶点和新策略。