MBL通过调控肝星状细胞的衰老抑制肝纤维化的作用机制

甘露聚糖结合凝集素 (mannan/mannose-binding lectin, MBL) 是肝脏产生的重要天然免疫分子。我们的前期研究提示MBL可通过对肝脏免疫微环境的调控影响相关肝脏疾病的进展。最近发现，在四氯化碳诱导的小鼠肝纤维化模型中，与野生型小鼠（WT）相比，MBL缺陷小鼠（MBL-/-）的肝纤维化程度更高、肝内衰老的肝星状细胞(HSC)更少；体外实验亦发现MBL能促进HSC的衰老。据此提出假说：MBL可通过调节HSC的活化-衰老-凋亡的平衡来影响肝纤维化进展。拟开展以下研究：①动物：在小鼠肝纤维化模型中研究MBL调节HSC的活化-衰老-凋亡的调控网络及其与肝纤维化的进展的关系；②体外：MBL对HSC的调控机制，探索其中的关键分子；③临床：MBL与关键细胞、关键分子及肝纤维化进展的关系。所得结果将丰富MBL生物学功能的基础理论，并为相关肝病的防治提供新靶点，亦为MBL缺损的肝病诊治提供新依据。

Mannan (or mannose)-binding lectin (MBL), mainly produced by hepatocye, is instrumental in the innate immune system. Our previous studies have indicated that MBL might impact on liver disease development by shaping the liver microenvironment via its interaction with immune cells or the local stromal cells. Recently, we observed that genetic MBL ablation in mice could exacerbate carbon tetrachloride (CCl4)-induced liver fibrosis. Hepatic stellate cells (HSC) senescence declined in MBL-deficient mice compared with WT mice. In vitro study demonstrated that MBL could promote HSC senescence in HSC cell line LX-2. On the basis of these findings, we propose the present grant. The regulation mechanism of MBL on the activation, senescence and apoptosis of HSC and its effect on liver fibrosis will be studied. The HSC function, NK cells, macrophage were compared between wild-type and MBL deficient mice in CCl4-induced liver fibrosis model. The signal transduction and the underlying mechanisms will be investigated in vitro. Human liver tissues and blood from patients with liver fibrosis and healthy participants will be collected. The cell-cell interaction will be investigated, and the association among MBL and disease severity will be analyzed. The study will elucidate the relationship among MBL, HSC, macrophage function, NK cells and the pathogenesis of liver fibrosis, which provides a new understanding about the function of MBL and regulation of HSC senescence. Additionally, this study will substantiate the concept that MBL is a vital regulator of liver microenvironment, thus making it a potential target for modulation in the clinical settings of liver fibrosis associated disease, and providing new therapeutic strategy for the treatment of liver disease in patients with MBL deficiency.