巨噬细胞极化调节肝星状细胞自噬在非酒精性脂肪性肝病发病中的作用

Hepatic stellate cells (HSCs) autophagy has a crucial role in the pathogenesis of alcoholic fatty liver disease (NAFLD). Our previous study found that there was more prominent activation of M1 macrophages than M2 macrophages in the liver of mice NAFLD model. Notch signaling pathways regulating macrophage polarization has a close relationship with HSCs activation. However, there is a lack of data on the polarization of macrophages and regulation of HSCs autophagy in NAFLD. In the present study, in macrophages and HSCs co-cultured system, or in NAFLD mice, we increase Notch levels by transgenic technology or decrease their levels by siRNA interference technology to examine macrophages polarization, regulation of HSCs autophagy and the development of NAFLD. In summary, the study aims to investigate that there are complex interactions among Notch pathway, macrophages polarization, and HSCs autophagy, which may modify the outcome of NAFLD therapy, and therefore should be considered for the rational design of anti-NAFLD strategy.

肝星状细胞（HSCs）自噬被认为是非酒精性脂肪性肝病（NAFLD）发生、发展的关键环节。我们研究发现，NAFLD小鼠肝脏M1型巨噬细胞所占的比例显著高于M2型，Notch信号通路调节巨噬细胞极化与HSCs激活有密切关系。但Notch信号通路调节巨噬细胞极化与HSCs自噬参与NAFLD的具体作用机制尚需深入研究。本项目运用基因过表达和siRNA干扰技术干预Notch通路，调节巨噬细胞极化和巨噬细胞/HSCs共培养模型，观察其对HSCs自噬的影响，并进一步在NAFLD小鼠模型中观察阻断Notch信号通路对HSCs自噬及NAFLD疾病进程的影响。本项目旨在探讨Notch通路、巨噬细胞极化与HSCs自噬、NAFLD发病的关系，为可能的靶向治疗提供理论依据。

非酒精性脂肪性肝病（NAFLD）发病机制尚不清除，尚无有效治疗药物。肝星状细胞（HSCs）自噬被认为是NAFLD发生、发展的关键环节。我们研究发现，肝脏巨噬细胞极化调节肝星状细胞自噬，促进肝纤维化形成。然而，巨噬细胞调节肝星状细胞自噬的机制目前尚不清楚，Notch信号通路调节巨噬细胞极化与HSCs激活有密切关系。但Notch信号通路调节巨噬细胞极化与HSCs自噬参与NAFLD的具体作用机制尚需深入研究。本项目通过体外实验调节巨噬细胞极化和巨噬细胞/HSCs共培养模型，观察其对HSCs自噬的影响，并进一步在NAFLD小鼠模型中观察阻断Notch信号通路对HSCs自噬及NAFLD疾病进程的影响。结果显示，NAFLD小鼠肝星状细胞自噬和激活增强，M1型巨噬细胞对HSCs自噬和激活无明显作用。在巨噬细胞/HSCs共培养体系中，M2型巨噬细胞分泌的细胞因子PGE2促进HSCs自噬和激活，同时 M2型巨噬细胞共培养的HSCs高表达PGE2受 EP4蛋白.在NAFLD小鼠模型中，M2型巨噬细胞通过Notch1/PGE2/EP4途径促进HSCs自噬和激活。阻断EP4受体能有效缓解NAFLD小鼠肝纤维化。通过探讨Notch通路、巨噬细胞极化与HSCs自噬、NAFLD发病的关系，为NAFLD的靶向治疗提供理论依据。