病理损伤修复中肺脏和肠道区域免疫特性对比分析及潜在功能关联分析

Although gut microbiota and its associated gut immunity have been the recent hot topic of investigation, there is much less study of lung microbiota and its associated lung immunity. Dysregulated gut microbiota is involved in the pathogenesis of multiple gut diseases such as colitis and colon cancer, and is also reported to be involved in the disease pathogenesis in other tissues such as liver and brain. However, it is not clear if gut microbiota dysregulation affects lung disease development. This grant proposal is to comparatively analyze the mechanisms of the respective microbiota to affect lung and gut local immunity during damage-induced disease pathogenesis, and explore if gut microbiota and its dysregulation affect lung microbiota and its related disease development. Four main research aims are comparative analyses and characterization of lung and gut microbiota species in regulation of Th17 cell development and IL-17 family cytokines expression during damage-mediated disease pathogenesis, comparative analyses and characterization of sensors and their pathways by those lung and gut microbiota species in regulation of respective local immunity, comparative investigations of functional mechanisms of IL-17 family cytokines in lung and gut disease pathogenesis, and analyses of the potential effects of gut microbiota and its dysregulation on lung microbiota, lung immunity and its associated disease development. The grant outcomes will provide important new information, targets and strategies for prevention and therapy of mucosal immunity associated diseases.

肠道菌群与肠道区域免疫特性已经成为近年来的研究热点，然而肺脏的菌群及区域免疫特性研究还很薄弱。肠道菌群紊乱参与多种肠道疾病的病理，也参与肠道之外其他组织如肝脏、脑等的疾病病理，但是否参与肺脏组织的疾病病理还不清楚。该申请拟对比分析肺脏和肠道粘膜组织损伤病理过程中各自微生态菌群对其区域免疫的影响机制以及探索肠道菌群及其紊乱是否影响到肺脏菌群及相关疾病病理。研究内容主要包括：1）对比分析鉴定在肺脏和肠道损伤病理进程中诱导Th17细胞分化和IL-17家族细胞因子表达的各自组织微生态菌群种类；3）对比分析鉴定在肺脏和肠道损伤病理进程中上述微生态菌群种类的识别受体及通路；3）对比分析研究IL-17家族细胞因子在肺脏和肠道粘膜组织损伤病理中的功能与作用机制；4）分析肠道菌群及其紊乱对肺脏微生态菌群、肺粘膜免疫及肺损伤性病理的影响。该项目研究成果将为粘膜免疫相关疾病的防治提供重要理论基础、新靶点与策略。

肺黏膜组织和肠道黏膜组织由于微环境的不同存在区域免疫功能特性，但其具体区域免疫功能机制还不够清楚。本项目对比分析肺脏和肠道黏膜组织损伤病理过程中各自区域免疫功能特性，发现肺部微生态菌群紊乱促进了小鼠模型肺炎症纤维化病理进程，且本底肠道菌群并不影响肺纤维化病理，肺部紊乱的革兰氏阴性菌通过产生外膜囊泡（OMV）作用于肺巨噬细胞中TLR受体诱导细胞因子IL-17B的产生，IL-17B接着作用于肺上皮细胞上IL-17RA和IL-17RB受体，诱导一系列细胞因子和趋化因子等基因表达，进而促进Th17细胞分化和肺炎症纤维化疾病病理，该研究结果表明肺组织和肠道组织中Th17诱导分化以及IL-17B的功能机制有所不同；发现调控肠道上皮内淋巴细胞（IEL）发育的新机制，肠道菌群特异性调控诱导型IEL发育，而食物来源的核酸通过天然免疫识别受体（STING和MAVS）通路特异性调控天然IEL的发育，天然IEL接着通过产生TGF-b1和TGF-b3促进肠道免疫耐受。该项目研究成果进一步阐明了肺和肠道黏膜区域特性的功能机制，肺脏呼吸微环境可能决定了肺部微生态的特性，进而影响到肺黏膜免疫功能特征和相关疾病病理，而肠道黏膜组织受到食物和微生态的双重微环境的影响，其共同调控肠道免疫稳态、耐受和相关疾病病理。