CHI3L1促进调节性T细胞减轻TAA导致的急性肝损伤的机制研究

The dysfunction of liver immune system play an important role in the pathogenesis of acute liver injury (ALI) which causes high incidence and mortality. CHI3L1 play an important role in tissue restoration while no research had been done between CHI3L1 and liver injury. Preliminary experiments showed that CHI3L1 protect the function of murine liver successfully in TAA induced ALI while increased regulatory T cells were observed. We also tested the level of CHI3L1 in patients, which proved that CHI3L1 are negatively correlated with ALT and AST level of liver. As no investigation had be done to the relationship between CHI3L1 and liver injury and Treg cells play an important role during the restoration of liver injury, we hypothesized that CHI3L1 protect TAA induced ALI through increasing Tregs. In this project, we plan to induce murine ALI by TAA, and CHI3L1-KO mice and MMP-9 KO mice as well as in vivo neutralizer will be used to evaluate the expression of CHI3L1, liver function and Treg percentage. We will also find out the relation between Treg and Th cell differentiation and CHI3L1 in vitro and vivo. Finally we will estimate how CHI3L1 maintain the liver function and the immunological mechanisms that CHI3L1 involved. The achievement of this project, will help us to understand the immunological mechanisms of CHI3L1 in ALI and provide us theoretical basis for clinical immunotherapy.

急性肝损伤(ALI)是多因素引起的常见肝脏损害，免疫功能紊乱扮演了非常重要的角色，几丁质酶3样蛋白（CHI3L1）参与组织修复，但是其在肝损伤中的作用和机制尚不清楚。预实验发现CHI3L1能够减轻硫代乙酰胺（TAA）导致的小鼠急性肝损伤并增加肝内调节性T细胞（Treg）；肝病患者血清CHI3L1水平随肝损伤程度加重而降低。由于Treg参与了肝损伤的修复，本课题假说CHI3L1能够通过促进肝脏内Treg数目和功能抑制T细胞免疫反应来保护肝细胞损伤，机制可能与星状细胞释放免疫因子MMP-9和TGF-β有关。本项目计划运用TAA诱导小鼠肝损伤并检测CHI3L1和Treg水平变化，在体内与体外环境去除Treg，MMP-9和TGF-β来明确CHI3L1的保护作用的细胞与分子信号机制。本研究将为治疗急性肝损伤提供新的治疗思路和理论依据。

急性肝损伤(ALI)是多因素引起的常见肝脏损害，免疫功能紊乱扮演了非常重要的角色。本项目自批准以来，围绕肝损伤的免疫学机制开展了多项研究，明确了T细胞亚群在肝损伤中的相关作用并阐明了多项机制；同时我们在多种疾病如器官移植免疫或移植物抗宿主病中围绕Treg的功能异常开展进一步研究。累计2018年以来以第一和通讯作者发表SCI文章12篇，其中标注文章4篇。主要研究成果如下：① 明确了CHI3L1在肝损伤中的作用和机制；② 发现酸性微环境对Treg分化和功能的影响进而调控肝损伤的作用；③ 报道了Treg失功能是导致自身免疫性肝病患者肝移植后原发病复发的重要原因；④ 阐明了IL-22调控Treg功能和GVHD发病率的可能机制。本研究将为治疗急性肝损伤提供新的治疗思路和理论依据。