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

Overview

Journal J Clin Transl Hepatol

Specialty Gastroenterology

Date 2024 Jul 12

PMID 38993513

Authors

Xiaoli Huang

Xiaofan Wang

Yanhong Wang

Shuangjun Shen

Wei Chen

Tianhui Liu

Ping Wang

Xu Fan

Lin Liu

Jidong Jia

Min Cong

Affiliations

Soon will be listed here.

Abstract

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.

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References

Siegmund S, Uchinami H, Osawa Y, Brenner D, Schwabe R . Anandamide induces necrosis in primary hepatic stellate cells. Hepatology. 2005; 41(5):1085-95. DOI: 10.1002/hep.20667. View

Asrani S, Devarbhavi H, Eaton J, Kamath P . Burden of liver diseases in the world. J Hepatol. 2018; 70(1):151-171. DOI: 10.1016/j.jhep.2018.09.014. View

Shan L, Wang F, Zhai D, Meng X, Liu J, Lv X . Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis. Biomed Pharmacother. 2023; 161:114472. DOI: 10.1016/j.biopha.2023.114472. View

Zhang J, Guo H, Zhang H, Wang H, Qian G, Fan X . Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene Friend leukemia virus integration 1 gene. Cancer. 2010; 117(1):86-95. PMC: 2995010. DOI: 10.1002/cncr.25522. View

Zhou Q, Rong C, Gu T, Li H, Wu L, Zhuansun X . Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway. Stem Cell Res Ther. 2022; 13(1):354. PMC: 9327397. DOI: 10.1186/s13287-022-03030-8. View

Schuppan D, Ashfaq-Khan M, Yang A, Kim Y . Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol. 2018; 68-69:435-451. DOI: 10.1016/j.matbio.2018.04.006. View

Chen L, Brenner D, Kisseleva T . Combatting Fibrosis: Exosome-Based Therapies in the Regression of Liver Fibrosis. Hepatol Commun. 2019; 3(2):180-192. PMC: 6357832. DOI: 10.1002/hep4.1290. View

Chen Y, Sun J, Liu J, Wei Y, Wang X, Fang H . Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis. J Immunother Cancer. 2023; 11(12). PMC: 10711917. DOI: 10.1136/jitc-2023-007487. View

Ghoshal-Gupta S, Kutiyanawalla A, Lee B, Ojha J, Nurani A, Mondal A . TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. Oncotarget. 2018; 9(10):8941-8956. PMC: 5823642. DOI: 10.18632/oncotarget.23832. View

10.

Cai X, Wang J, Wang J, Zhou Q, Yang B, He Q . Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacol Res. 2020; 155:104720. DOI: 10.1016/j.phrs.2020.104720. View

11.

Du J, Wan Z, Wang C, Lu F, Wei M, Wang D . Designer exosomes for targeted and efficient ferroptosis induction in cancer via chemo-photodynamic therapy. Theranostics. 2021; 11(17):8185-8196. PMC: 8344009. DOI: 10.7150/thno.59121. View

12.

Gao J, Wei B, Liu M, Hirsova P, Sehrawat T, Cao S . Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C-C Motif Chemokine Ligand 2-Mediated Angiocrine Signaling. Hepatology. 2020; 73(6):2468-2483. PMC: 8102654. DOI: 10.1002/hep.31617. View

13.

Sun M, Kisseleva T . Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015; 39 Suppl 1:S60-3. PMC: 4636085. DOI: 10.1016/j.clinre.2015.06.015. View

14.

Kisseleva T, Brenner D . Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2020; 18(3):151-166. DOI: 10.1038/s41575-020-00372-7. View

15.

Wu P, Liang J, Yu F, Zhou Z, Tang J, Li K . miR-145 promotes osteosarcoma growth by reducing expression of the transcription factor friend leukemia virus integration 1. Oncotarget. 2016; 7(27):42241-42251. PMC: 5173131. DOI: 10.18632/oncotarget.9948. View

16.

Filliol A, Schwabe R . FoxM1 Induces CCl2 Secretion From Hepatocytes Triggering Hepatic Inflammation, Injury, Fibrosis, and Liver Cancer. Cell Mol Gastroenterol Hepatol. 2020; 9(3):555-556. PMC: 7078446. DOI: 10.1016/j.jcmgh.2020.01.002. View

17.

Chen L, Chen R, Kemper S, Cong M, You H, Brigstock D . Therapeutic effects of serum extracellular vesicles in liver fibrosis. J Extracell Vesicles. 2018; 7(1):1461505. PMC: 5912192. DOI: 10.1080/20013078.2018.1461505. View

18.

Li Y, OuYang Q, Chen Z, Chen W, Zhang B, Zhang S . Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism. Hepatol Int. 2022; 17(3):636-647. DOI: 10.1007/s12072-022-10452-2. View

19.

Cong M, Liu T, Wang P, Fan X, Yang A, Bai Y . Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis. Am J Pathol. 2013; 182(5):1607-16. DOI: 10.1016/j.ajpath.2013.01.036. View

20.

Hu X, Ge Q, Zhang Y, Li B, Cheng E, Wang Y . A review of the effect of exosomes from different cells on liver fibrosis. Biomed Pharmacother. 2023; 161:114415. DOI: 10.1016/j.biopha.2023.114415. View