The different effects of four adenosine receptors in liver fibrosis
Background: The adenosine-adenosine receptor pathway plays a significant role in immune regulation and inflammation. There are four known adenosine receptors: A1R, A2AR, A2BR, and A3R. Interestingly, these receptors exhibit varying and even opposing functions in the progression of certain diseases. This study aims to explore the specific roles of A1R, A2AR, A2BR, and A3R activation in the development of liver fibrosis.
Methods: Liver fibrosis was induced in C57BL/6 mice through intraperitoneal injections of CCl4. To activate the respective adenosine receptors, the agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R, A2AR, A2BR, and A3R, respectively. Liver function was assessed by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Pathological liver damage was examined using hematoxylin and eosin (H&E) staining, while Masson and Sirius Red staining were utilized to evaluate collagen deposition. The proliferation and migration capabilities of hepatic stellate cells (HSCs) were assessed using CCK8 and scratch assays.
Results: In mouse models of liver fibrosis, activation of A1R and A2AR was found to exacerbate liver fibrosis, as evidenced by elevated ALT and AST levels, more severe liver tissue damage, and increased collagen deposition. In contrast, activation of A2BR and A3R led to a reduction in liver fibrosis. Additionally, A1R and A2AR agonists enhanced the proliferation and migration of the hepatic stellate cell line LX2, while A2BR and A3R agonists inhibited these processes. Consistently, treatment with A1R and A2AR agonists resulted in increased expression of α-SMA and Col1α1 in LX2 cells, whereas A2BR and A3R agonists suppressed their expression. Furthermore, 5′-N-ethyl-carboxamidoadenosine (NECA), a stable adenosine analog, was found to alleviate liver fibrosis and inhibit LX2 cell activity, proliferation, and migration.
Conclusion: This study highlights the distinct roles of A1R, A2AR, A2BR, and A3R in the progression of liver fibrosis through their regulatory effects on hepatic stellate cell activity and proliferation.