Abstract
Activated hepatic stellate cells (HSCs) release pro-inflammatory and pro-fibrogenic factors. CXC chemokine-ligand-1 (CXCL1) is expressed on HSCs. We previously found that the CD147 is overexpressed in activated HSCs. In this study, we showed an important role of CD147 in promoting liver fibrosis by activating HSCs and upregulating expression of chemokines. Specifically, we found that CD147 specific deletion in HSCs mice alleviated CCl4-induced liver fibrosis and inhibited HSCs activation. Overexpression of CD147 upregulated the secretion of CXCL1. Meanwhile, CXCL1 promoted HSCs activation through autocrine. Treating with PI3K/AKT inhibitor could effectively suppress CD147-induced CXCL1 expression. Taken together, these findings suggest that CD147 regulates CXCL1 release in HSCs by PI3K/AKT signaling. Inhibition of CD147 attenuates CCl4-induced liver fibrosis and inflammation. Therefore, administration of targeting CD147 could be a promising therapeutic strategy in liver fibrosis.
Highlights
Liver fibrosis can be caused by hepatitis B virus or hepatitis C virus infection, alcohol, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, and other relatively rare conditions, such as autoimmune hepatitis, Wilson’s disease, and primary/secondary biliary cholangitis
Hepatic stellate cells (HSCs) activate into α-SMA+ contractile myofibroblast-like cells, which are characterized by the increased proliferation and migration, the unbalanced matrix degradation and the release of pro-inflammatory and pro-fibrogenic factors [2]
An increase of CXC chemokine-ligand-1 (CXCL1) cytoplasm expression was observed in the activated HSCs that were positive for α-SMA in CCl4-induced mouse liver tissues (Figure 1C)
Summary
Liver fibrosis can be caused by hepatitis B virus or hepatitis C virus infection, alcohol, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, and other relatively rare conditions, such as autoimmune hepatitis, Wilson’s disease, and primary/secondary biliary cholangitis. Sustained chronic liver injury leads to normal cellular functional disruption and imbalance of the degradation and synthesis of extracellular matrix (ECM), which eventually develops the liver fibrosis [1]. HSCs activate into α-SMA+ contractile myofibroblast-like cells, which are characterized by the increased proliferation and migration, the unbalanced matrix degradation and the release of pro-inflammatory and pro-fibrogenic factors [2]. HSCs have immunological functions—they express functional chemokine receptors and chemokines, including CXCL1, CXCL8, CXCL9, CXCL10, CCL2, CCL3 and CCL5 [3]. CXC chemokine-ligand-1 (CXCL1), known as Gro-alpha, is a ligand for G-protein-coupled receptor CXCR2. CXCL1 is considered to be involved in the activation of HSCs [4], fibrogenesis and angiogenesis [5,6]. CXCL1 has been recognized as a biomarker associated with hepatocellular carcinoma in a serum level [7]
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