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P2X7R orchestrates the progression of murine hepatic fibrosis by making a feedback loop from macrophage to hepatic stellate cells.
- Source :
-
Toxicology letters [Toxicol Lett] 2020 Oct 15; Vol. 333, pp. 22-32. Date of Electronic Publication: 2020 Jul 25. - Publication Year :
- 2020
-
Abstract
- HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.<br />Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Cell Culture Techniques
Cell Line, Tumor
Chemical and Drug Induced Liver Injury pathology
Disease Models, Animal
Extracellular Matrix drug effects
Extracellular Matrix metabolism
Feedback, Physiological
Hepatic Stellate Cells metabolism
Hepatic Stellate Cells pathology
Humans
Liver Cirrhosis pathology
Macrophages, Peritoneal metabolism
Macrophages, Peritoneal pathology
Male
Mice
Mice, Inbred C57BL
Purinergic P2X Receptor Antagonists pharmacology
Pyridines pharmacology
Tetrazoles pharmacology
Thioacetamide toxicity
Chemical and Drug Induced Liver Injury metabolism
Hepatic Stellate Cells drug effects
Liver Cirrhosis metabolism
Macrophages, Peritoneal drug effects
Receptors, Purinergic P2X7 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3169
- Volume :
- 333
- Database :
- MEDLINE
- Journal :
- Toxicology letters
- Publication Type :
- Academic Journal
- Accession number :
- 32721574
- Full Text :
- https://doi.org/10.1016/j.toxlet.2020.07.023