肝脏缺血再灌注后IL-17A信号对肝损伤和后期肝修复的影响和机制

The intrahepatic immune system which activated by hepatic ischemia-reperfusion(IR) injury aggravated liver damage and released important cytokines to help initiation of liver healing. IL–17A is one of the most important immune factors in liver IR injury, which also has been confirmed recently as an indispensable cytokines in liver repair. The dual function of IL-17 is worthy to probe to reveal the exact immune mechanisms underlying liver IR. In this project, IL-17-GFP mice will be used to determine the cell source of IL-17A after liver IR. The role of HMGB1 in IL-17A expression will also be investigated in vivo. Preliminary experimental results concluded that the effect of IL-17A on Kupffer cells (KCs) and hepatic stellate cells (HSCs) may be the main cause of liver injury and healing. With the chimeric mice IR model in vivo, the activation of KCs and HSCs without the presence of IL-17A will be measured and the severity and healing effect of liver will be evaluated. Moreover, the molecular mechanism of IL-17A in activating KCs and HSCs will be studied. This project will be advantageous to the systematic analysis of liver immune modulation after IR, especially the upstream and downstream signal of IL-17A during liver injury and healing, and to seek new target and proper phase for clinical therapy.

肝缺血再灌注（ischemia/reperfusion，IR）损伤通过激活肝内免疫系统加重肝损伤，同时释放启动肝修复的重要因子。IL-17A是肝IR损伤中的重要免疫因子之一，近期亦被证实在肝脏修复中不可或缺，明确IL-17A的双重作用对于探究其参与肝IR后的确切免疫机制显得尤为重要。本项目采用GFP-IL-17A小鼠分析IR后肝内IL-17A细胞来源和上游信号。由预实验结果推断IL-17A对Kupffer细胞（KCs）和肝星状细胞（HSCs）的影响，可能是其参与肝损伤和修复的主要原因；体内实验通过嵌合鼠肝IR模型，分析在缺乏IL-17RA信号时KCs和HSCs的激活情况，以及肝损伤和修复相关指标变化，进一步研究其激活KCs和HSCs的IL-17RA信号通路。本项目系统分析肝脏IR免疫微环境中，IL-17A产生的上游信号，及其激活肝内细胞参与肝损伤和修复的下游信号机制，以期指导临床干预治疗。

肝缺血再灌注（ischemia/reperfusion，IR）损伤通过激活肝内免疫系统加重肝损伤，同时释放启动肝修复的重要因子。IL-17A是肝IR损伤中的重要免疫因子之一，近期亦被证实在肝脏修复中不可或缺，明确IL-17A的双重作用对于探究其参与肝IR后的确切免疫机制显得尤为重要。本项目采用GFP-IL-17A小鼠分析IR后肝内IL-17A细胞来源和上游信号。由预实验结果推断IL-17A对Kupffer细胞（KCs）和肝星状细胞（HSCs）的影响，可能是其参与肝损伤和修复的主要原因；体内实验通过嵌合鼠肝IR模型，分析在缺乏IL-17RA信号时KCs和HSCs的激活情况，以及肝损伤和修复相关指标变化，进一步研究其激活KCs和HSCs的IL-17RA信号通路。研究发现KCs中参与肝脏损伤修复的重要信号机制：1）Notch信号，其缺乏可减轻肝损伤，其机制是增加Hers1，促进RhoA/ROCK活化；2）TGR5信号，该信号可通过激活TLR4–NF-kB保护肝损伤。这两条信号通路均通过促进IL-17生成参与了肝损伤与修复。相关工作发表SCI论文7篇，包括NAV REV IMMUNOL, HAPATOLOGY, BLOOD，CELL MOL IMMUNOL等国际一流期刊。研究成果获江苏省科学技术奖一等奖，南京市科技进步奖一等奖各2项。