可溶性MULT1通过活化肝脏固有淋巴细胞调控血吸虫病肝纤维化的机制研究

干预肝纤维化进程可显著改善晚期血吸虫病人的生存质量。血吸虫产卵后引起的HSC活化并转分化为成肌纤维细胞是肝纤维化发生的中心环节，肝脏NK细胞能多途径调控HSC。NKG2D 是肝脏NK细胞上的主要活化受体，血吸虫感染能影响HSC的NKG2DLs水平和NK细胞NKG2D水平。前期研究发现，血吸虫病人血清中可溶性NKG2DLs的水平升高；过表达sMULT1可改善血吸虫病小鼠的肝纤维化，并伴有脾NK细胞上NKG2D的表达上调及肝、血清IFN-γ的升高。本项目拟研究肝脏NK细胞在血吸虫病肝纤维化中的作用，利用诱导性肝脏过表达sMULT1基因修饰小鼠，明确感染血吸虫后sMULT1对NK细胞和其它ILC亚群的影响以及sMULT1活化NK细胞后调控HSC的具体机制，为阐明肝脏ILCs对血吸虫病肝纤维化进程和转归的影响提供理论依据，并为探寻纤维化治疗的新靶点提供思路和实验依据。

Intervention of liver fibrosis can significantly improve the life quality of patients with advanced schistosomiasis. The activation and the trans-differentiation of hepatic stellate cells into myofibroblasts is the critical event during the formation of liver fibrosis due to the deposition of schistosome eggs. Recent studies have shown that liver NK cells can impact the activated hepatic stellate cells in various ways. NKG2D is a major activating receptor of NK cells, it was reported that both NKG2D and its ligend (NKG2DLs) were markedly modulated after schistosome infection. Our preliminary data indicated an increased level of sMICA, a soluble NKG2DL in human, in sera from schistosomiasis patients, administration of the plasmid loaded with the recombinant sMULT1 alleviated the hepatic fibrosis progress in mice infected with Schistosoma japonicum, and an elevated expression of NKG2D on the NK cells was also detected, which was consistent with the elevated IFN-γ level in serum and enhanced IFN-γ secretion by NK cells in spleen. Our proposal is designed with genetically modified mice with sMULT1 over expression in liver to explore the role of hepatic ILCs, including the NK cells, in regulation of schistosomiasis liver fibrosis. The phenotype and the function of liver ILC1 subgroups would also be measured. The goal of these surveys is to form the cells and cytokines network involved in the regulatory effect of sMULT1 on hepatic fibrosis caused by schistosomiasis. Our research will clarify a novel mechanism of the liver ILCs in schistosomiasis liver fibrosis process and provide theoretical basis for the development of the new therapeutic target on liver fibrosis.