School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Phytomedicine. 2023 Oct;119:155016. doi: 10.1016/j.phymed.2023.155016. Epub 2023 Aug 7.
Liver fibrosis caused by chronic liver injury, eventually develops into liver cirrhosis and hepatocellular carcinoma. Currently, there are no effective drugs to relieve liver fibrosis due to the lack of molecular pathogenesis characteristics. Former research demonstrates that the hepatic immune microenvironment plays a key role in the pathogenesis of liver fibrosis, thus macrophages are important immune cells in the liver. Our previous study has found that IDO1 plays an important role in the liver immune microenvironment. CRG is a gallic acid tannin found in medicinal plants of many ethnicities that protects against inflammation, tumors and chronic liver disease. However, the mechanism of by which CRG mediates the interaction of IDO1 with macrophages during hepatic immune maturation is not clear.
To investigate the regulatory mechanism of CRG in liver fibrosis and the intrinsic relationship between IDO1 and macrophage differentiation.
Zebrafish, RAW264.7 cells and mice were used in the study. IDO1 overexpression and knockdown cell lines were constructed using lentiviral techniques.
We discovered that CRG remarkably reduced the AST and ALT serum levels. Histological examination revealed that CRG ameliorates CCL4-induced liver fibrosis and depressed the expression of α-SMA, Lamimin, Collagen-Ι and fibronectin. Besides, we found that CRG promoted increased MerTK expression on partly macrophages. Interestingly, in vitro, we found that CRG suppressed IDO1 expression and regulated macrophage differentiation by upregulating CD86, CD80 and iNOS, while downregulating CD206, CD163, IL-4 and IL-10 expression. Additionally, we found that CRG could inhibit hepatic stellate cell activation by direct or indirect action.
Our findings suggest that CRG alleviates liver fibrosis by mediating IDO1-mediated M2 macrophage repolarization.
慢性肝损伤导致的肝纤维化，最终会发展为肝硬化和肝细胞癌。目前，由于缺乏分子发病机制特征，尚无有效药物来缓解肝纤维化。先前的研究表明，肝免疫微环境在肝纤维化发病机制中起着关键作用，因此巨噬细胞是肝内的重要免疫细胞。我们之前的研究发现 IDO1 在肝免疫微环境中发挥着重要作用。CRG 是一种在许多民族的药用植物中发现的没食子酸单宁，可预防炎症、肿瘤和慢性肝病。然而，CRG 介导 IDO1 与巨噬细胞在肝免疫成熟过程中的相互作用的机制尚不清楚。
研究 CRG 在肝纤维化中的调节机制以及 IDO1 与巨噬细胞分化之间的内在关系。
使用斑马鱼、RAW264.7 细胞和小鼠进行研究。使用慢病毒技术构建 IDO1 过表达和敲低细胞系。
我们发现 CRG 显著降低了血清 AST 和 ALT 水平。组织学检查显示，CRG 可改善 CCL4 诱导的肝纤维化，并降低 α-SMA、层粘连蛋白、胶原-Ι 和纤维连接蛋白的表达。此外，我们发现 CRG 促进了部分巨噬细胞上 MerTK 的表达增加。有趣的是，在体外，我们发现 CRG 通过上调 CD86、CD80 和 iNOS，同时下调 CD206、CD163、IL-4 和 IL-10 的表达，抑制 IDO1 的表达并调节巨噬细胞分化。此外，我们发现 CRG 可以通过直接或间接作用抑制肝星状细胞的激活。
我们的研究结果表明，CRG 通过调节 IDO1 介导的 M2 巨噬细胞极化来缓解肝纤维化。
