MIG诱导Treg/Th17失衡促非酒精性脂肪性肝病发展的作用及其机制研究

Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver diseases, but its mechanism is still unclear. The persistent inflammation caused by proinflammatory cytokines is considered to be a key factor in the pathogenesis of NAFLD. Chemokines are important members of proinflammatory cytokines. Our results showed that chemokine MIG were overexpressed in patients and animal models with nonalcoholic steatohepatitis (NASH). Recent studies have shown that Treg/Th17 imbalance plays a significant role in the development of NASH, and IL-6 is the pivotal molecule to induce the differentiation of Treg and Th17 cells. In our previous study, we found that MIG induced the expression of IL-6 in liver specimens and phosphorylated JNK protein in hepatocytes. This suggests that MIG may promote the progression of NAFLD, but its mechanism is unknown. In this current proposed project, we aimed to confirm the relationship between MIG/CXCR3 and NAFLD, and investigate the role of Treg/Th17 imbalance regulated by MIG in the progression of NAFLD. Moreover, we explored the molecular mechanism involved in MIG induced IL-6 production, and clarified the relation with Treg/Th17 differentiation. The results of this study will helpful for early intervention of NAFLD.

非酒精性脂肪性肝病（NAFLD）是最常见慢性肝病，发病机制仍不明确。持续肝脏炎症决定着NAFLD发展，其发病机制关键环节是促炎细胞因子，趋化因子是促炎细胞因子重要成员。我们预实验显示，趋化因子MIG在非酒精性脂肪性肝炎（NASH）患者及动物模型体内表达显著升高。新近研究表明，Treg/Th17失衡在NASH发生发展中起重要作用，IL-6是诱导Treg及Th17细胞分化的关键因子。我们前期研究显示，MIG诱导肝组织中IL-6及细胞中磷酸化JNK蛋白表达上调，提示MIG可促进NAFLD进展，但机制不明。本项目拟通过体内外进一步研究证实MIG及其受体与NAFLD的关系；验证MIG通过调控 Treg/Th17失衡促进NAFLD的进展；研究MIG对IL-6分泌的调控作用及分子机制，明确其与Treg和Th17分化的关系，阐明MIG在NAFLD中的作用、分子机制，以期为NAFLD早期干预寻找到潜在靶点。

非酒精性脂肪性肝病（NAFLD）的全球发病率增长迅速且呈低龄化趋势，但其发病机制至今仍未完全清楚。新近研究表明Treg/Th17免疫细胞失衡在非酒精性脂肪肝（NAFL）进展为非酒精性脂肪性肝炎（NASH）中发挥重要作用。细胞因子在调控Treg和Th17细胞分化方面起关键作用，而趋化因子MIG是重要的致炎性因子之一。在本项目中我们对趋化因子MIG、Treg/Th17和NAFLD发展三者之间的关系进行了探究。我们的研究显示在NASH患者和小鼠模型中，MIG表达明显升高，Treg细胞比例减少，Th17细胞比例增多。通过在NASH小鼠中使MIG稳定低表达，我们证实MIG可加重NASH的进展，抑制Treg细胞分化，促进Th17细胞分化，导致Treg/Th17失衡。此外，在体外细胞培养实验中MIG刺激可直接抑制Treg细胞分化并促Th17细胞分化，并且还发现MIG可促进Th17细胞的增殖，该作用呈浓度依赖性。通过进一步机制研究我们发现MIG可增加JNK信号通路关键蛋白JNK的磷酸化，提示其可能通过这一通路发挥作用。本项目证实了MIG可通过诱导Treg/Th17失衡促进NAFLD的发展，为NAFLD的早期干预提供了一个新思路，但更具体的分子机制需要后续项目进一步研究探索。