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

Autor:	Huang X; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Wang X; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Wang Y; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.; Dongying People's Hospital, Dongying, Shandong, China., Shen S; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Chen W; Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China., Liu T; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Wang P; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Fan X; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Liu L; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Jia J; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China., Cong M; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.
Jazyk:	angličtina
Zdroj:	Journal of clinical and translational hepatology [J Clin Transl Hepatol] 2024 Jul 28; Vol. 12 (7), pp. 634-645. Date of Electronic Publication: 2024 Jun 11.
DOI:	10.14218/JCTH.2023.00514
Abstrakt:	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 adeno-associated 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 siRNA-TIMP-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 miRNA-145-enriched 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. Competing Interests: JJ has been an Executive Associate Editor of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication. (© 2024 Authors.)
Databáze:	MEDLINE
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