CXCL12-CXCR4/CXCR7信号轴在肝再生和肝纤维化中的作用

Role of CXCL12-CXCR4/CXCR7 signal axis in liver regeneration and liver fibrosis

趋化因子CXC配体12(CXCL12)-趋化因子CXC受体4(CXCR4)信号轴参与调控肝损伤修复和肝纤维化的发生与发展。急慢性肝损伤时,CXCL12表达上调,募集CXCR4阳性免疫细胞向肝脏迁移。CXCL12-CXCR4通路通过促进肝星状细胞的活化和增殖参与肝纤维化的发生。CXCR4小分子抑制剂的出现使该受体成为抗纤维化治疗的一个有吸引力的靶点。目前,CXCR4已经被尝试用于多种脏器纤维化包括肺纤维化、慢性胰腺炎等抗纤维化治疗的靶点。但是部分研究显示单纯阻断CXCL12/CXCR4轴并不能改善肝纤维化,甚至加重肝损伤。近年来随着CXCR12另一受体CXCR7的发现和认识,CXCR4促纤维化通路和CXCR7促再生通路在肝再生和肝纤维化中的相互制衡作用得以阐释。充分认识CXCL12-CXCR4/CXCR7通路在肝病中的调控机制,并据此开展靶向治疗研究,实现CXCR4和CXCR7的再平衡,有望成为肝纤维化治疗的新策略。

Chemokinc CXC ligand 12(CXCL12)-chemokine receptor 4(CXCR4)signal axis is involved in the regulation of liver injury repair and the occurrence and development of liver fibrosis.In case of acute and chronic liver injury,the expression of CXCL12 is up-regulated to collect CXCR4-positive immune cells to migrate to the liver.The CXCL12-CXCR4 pathway participates in the occurrence of liver fibrosis by promoting the activation and proliferation of hepatic stellate cells.The emergence of small molecule inhibitors of CXCR4 makes this receptor an attractive target for anti-fibrosis therapy.At present,CXCR4 has been tried as an antifibrosis treatment targets for fibrosis of various organs,including pulmonary fibrosis and chronic pancreatitis.However,some studies have shown that simply blocking the CXCL12/CXCR4 axis cannot improve liver fibrosis and even aggravate liver injury.In recent years,with the discovery and understanding of CXCR7,another receptor of CXCR12,the counteracting role of CXCR4-promoting fibrosis pathway and CXCR7-promoting regeneration pathway in liver regeneration and liver fibrosis has been interpreted.Therefore,a full understanding of the regulatory mechanism of CXCL12-CXCR4/CXCR7 pathway,the development of corresponding targeted therapy research for liver disease,and the rebalancing of CXCR4 and CXCR7 are expected to become a new strategy for the liver fibrosis therapy.