TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental Liver Fibrosis  

作　　者：Xiaoli Huang Xiaofan Wang Yanhong Wang Shuangjun Shen Wei Chen Tianhui Liu Ping Wang Xu Fan Lin Liu Jidong Jia Min Cong 

机构地区：[1]Liver Research Center,Beijing Friendship Hospital,Capital Medical University,Beijing,China [2]Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease,Beijing,China [3]Dongying People’s Hospital,Dongying,Shandong,China [4]Experimental and Translational Research Center,Beijing Friendship Hospital,Capital Medical University,Beijing,China

出　　处：《Journal of Clinical and Translational Hepatology》2024年第7期634-645,共12页临床与转化肝病杂志（英文版）

基　　金：supported by a grant from the National Natural Science Foundation of China(grant numbers 81570542 and 82170614);the WBE Liver Fibrosis Foundation(grant number CFHPC2021042).

摘　　要：Background and Aims:Tissue inhibitor of metalloproteinase-1(TIMP-1)plays a role in the excessive generation of extracellular matrix in liver fibrosis.This study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1(MCP-1)expression and promotes hepatic macrophage recruitment.Methods:Liver fibrosis was triggered through carbon tetrachloride,and an adenoassociated virus containing small interfering RNA targeting TIMP-1(siRNA-TIMP-1)was administered to both rats and mice.We assessed the extent of fibrosis and macrophage recruitment.The molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays,luciferase reporter assays,the use of pharmacological modulators,and an analysis of extracellular vesicles(EVs).Results:siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis,reducing macrophage migration and MCP-1 expression.Co-culturing macrophages with hepatic stellate cells(HSCs)post-TIMP-1 downregulation inhibited macrophage migration.In siRNATIMP-1-treated HSCs,microRNA-145(miRNA-145)expression increased,while the expression of Friend leukemia virus integration-1(Fli-1)and MCP-1 was inhibited.Downregulation of Fli-1 led to decreased MCP-1 expression,whereas Fli-1 overexpression increased MCP-1 expression within HSCs.Transfection with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1,while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in HSCs.miRNA-145 bound directly to the 3'-UTR of Fli-1,and mi RNA-145-EN-riched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage recruitment.Conclusions:TIMP-1 induces Fli-1 expression through miRNA-145,subsequently increasing MCP-1 expression and macrophage recruitment.MiRNA-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.

关 键 词：TIMP-1 FLI-1 MCP-1 miRNA-145 Liver fibrosis Extracellular vesicles 

分 类 号：R575[医药卫生—消化系统]