白介素25经巨噬细胞对非酒精性脂肪肝的阻断作用及其机制

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and closely associated with metabolic syndrome, liver fibrosis and liver cancer, for which there is no satisfactory treatment presently. It is well established that alternatively activated (M2) Kupffer cell, which is induced by Th2 immunity, is negatively associated with liver injury in NAFLD. Interleukin-25 (IL-25) could promote the release of IL-5, IL-10 and IL-13 from macrophages and initiate Th2 immunity. Our previous study showed that IL-25 could reduce the body weight and ameliorate liver injury in mice fed with high fat diet (HFD). We hypothesized that IL-25 may protect HFD fed mice against NAFLD through the activation of M2 Kupffer cell. In the present grant proposal, we will first observe the relationship between IL-25 level and liver steatosis. Then we will use macrophage depletion mice, macrophage transferred mice and cell model to investigate the detailed mechanism of IL-25 on the protection of NAFLD and the role of Kupffer cell in the mechanism, We will also use clinical samples to confirm the relationship between IL-25 level and downstream cytokines and activation of M2 Kupffer cell and liver injury in both serum and liver tissue of NAFLD patients. Our study will provide a novel insight into how IL-25 ameliorates NAFLD and explore new pharmaceutical targets for the treatment of NAFLD.

非酒精性脂肪肝（NAFLD）是常见肝病，和代谢综合征、肝纤维化及肝癌关系密切，但目前无特效治疗。Th2型免疫反应诱导的M2型Kupffer细胞能减轻NAFLD病变。白介素（IL）25能促使巨噬细胞分泌IL-5、IL-10和IL-13等细胞因子并能诱导Th2型免疫反应。我们前期研究发现，IL-25能减轻高脂饮食喂养的小鼠体重和NAFLD病变程度。因此IL-25可能是通过诱导Th2型免疫反应和M2型Kupffer细胞分化缓解NAFLD。本研究将在前期工作基础上，首先观察NAFLD患者体内IL-25水平与肝脏病变程度的关系，进而通过去巨噬细胞小鼠模型、巨噬细胞移植小鼠模型和细胞模型探讨IL-25通过Kupffer 细胞阻断NAFLD的分子机制，最后在患者体内验证IL-25及下游细胞因子水平和M2型Kupffer、肝脏病变程度的关系，期望为NAFLD治疗开辟新途径。

非酒精性脂肪肝（NAFLD）是常见慢性肝病，和代谢综合征、肝纤维化及肝癌关系密切，但发病机制尚不清楚，并缺乏特异治疗药物。Th2型免疫反应诱导的M2型Kupffer细胞能减轻NAFLD病变。白介素（IL）25能促使巨噬细胞分泌IL-5、IL-10和IL-13等细胞因子并能诱导Th2型免疫反应。我们的研究从临床标本、细胞模型、动物模型等多个层次发现，IL-25水平和高脂饮食（HFD）诱导的NAFLD脂肪沉积严重程度呈负相关；外源性IL-25通过IL-25/IL-13/STAT6/M2a型巨噬细胞轴抑制NAFLD的发展，并通过促进肝细胞内STAT6和IL-25启动子结合，促进肝细胞内源性表达IL-25增加。本研究阐明了IL-25抑制NAFLD的细胞机制和分子机制，为NAFLD新药开发提供实验依据,期望能为NAFLD药物治疗开辟新途径。