肝脏TRPM2-CCL7/CCR1轴招募脾源性单核-巨噬细胞调控肝区域免疫重塑的作用及机制

慢性肝病时肝脏从外周循环招募单核-巨噬细胞参与肝脏免疫调控。利用脾移植小鼠模型，我们发现脾脏是纤维化肝脏中聚集的单核-巨噬细胞的重要来源；肝脏巨噬细胞高表达CCL7，其中招募自脾脏的单核-巨噬细胞高表达CCR1；TRPM2钙离子通道活化可上调CCL7表达。故推测：纤维化肝脏巨噬细胞中TRPM2活化，上调 CCL7表达，增加对脾源性CCR1高表达单核-巨噬细胞的招募，调控肝脏区域免疫重塑，形成促进肝病进展的局部微环境。本课题拟以肝纤维化小鼠为研究对象，利用脾移植、细胞过继回输、抗体封闭等明确CCL7/CCR1在肝脏募集脾脏单核-巨噬细胞中的作用；借助TRPM2缺失/诱导、TRPM2基因敲除小鼠等解析TRPM2对CCL7的表达调控，并结合肝硬化临床样本检测，分析TRPM2-CCL7/CCR1介导的脾源性单核-巨噬细胞招募对肝区域免疫及肝病进展的调控。结果将为临床慢性肝病治疗提供新靶点。

In chronic liver disease, the liver recruits monocyte derived macrophages (MoMFs) from the peripheral circulation to participate in liver immune regulation. In our previous study, we constructed the spleen transplantation model in liver fibrosis mice, and found that the spleen is an important source of aggregated MoMFs in the fibrotic liver. Further analysis showed that the chemokine CCL7 was highly expressed on liver macrophages, while its receptor CCR1 was highly expressed on the spleen-derived MoMFs. We also verified that activation of TRPM2 calcium ion channel up-regulated the expression of CCL7.Therefore, we speculate that macrophages in the fibrotic liver up-regulate the expression of CCL7 through activation of TRPM2, and this increases the recruitment of spleen-derived CCR1 highly expressed MoMFs. This process will regulate the liver immune remodeling and thus promote the progression of chronic liver disease. This study intends to use spleen transplantation, antibody blocking and in vitro chemotaxis to clarify the effect of CCl7/CCR1 signal on the recruitment of spleen-derived MoMFs by the liver. Then elucidate the role of TRPM2 in regulating the secretion of CCL7 by means of TRPM2 deletion/induction and TRPM2 knockout mice construction. And further analyze the correlation between TRPM2-CCL7/CCR1 mediated spleen-derived MoMFs recruitment and the regulation of liver region immunity. The results of this study will provide new targets for the clinical treatment of chronic liver disease.