Introduction
Liver diseases encompass a broad spectrum of conditions ranging from acute hepatitis and liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC). These conditions are often characterized by inflammatory responses where chemokines, particularly C-C motif ligand 5 (CCL5), play pivotal roles. CCL5, also known as RANTES (regulated on activation, normal T cell expressed and secreted), is a small cytokine involved in the recruitment and activation of immune cells. This review explores the multifaceted role of CCL5 in liver diseases, its mechanisms of action, and potential therapeutic applications.
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Fig. 1 CCL5 mediates hepatic injury and promotes fibrosis and HCC development by modulating hepatic inflammation (Chen L., et al. 2020).
CCL5 and Liver Diseases
Hepatic Ischemia/Reperfusion (IR) Injury
Hepatic IR injury, a significant concern in liver resection and transplantation, is characterized by blood flow restoration after ischemia. This process triggers the activation of Kupffer cells and neutrophils, releasing inflammatory cytokines and reactive oxygen species that aggravate liver damage. Elevated CCL5 levels have been found in IR injuries of various tissues, including the liver. Studies indicate that CCL5 promotes macrophage infiltration and pro-inflammatory responses, exacerbating IR injury. Strategies targeting CCL5, such as immunoneutralization or administration of CCL5 antagonists, have shown promise in reducing IR injury, suggesting CCL5 as a novel therapeutic target in clinical procedures.
Acute Liver Failure (ALF)
ALF, or fulminant hepatic failure, is a severe and often reversible liver injury with a high mortality rate. CCL5 plays a critical role in the pathogenesis of ALF. In patients undergoing liver transplantation for ALF, elevated CCL5 levels in the transplanted liver suggest its involvement in the disease process. Additionally, studies have shown increased CCL5 expression in patients with acute liver failure compared to those with acute non-fulminant hepatitis or chronic liver disease. CCL5 contributes to the recruitment and activation of macrophages, further aggravating liver injury. In acetaminophen (APAP)-induced acute liver injury, CCL5 has been implicated in exacerbating the condition. CCL5 deficiency protects against APAP-induced death, and the administration of CCL5-neutralizing antibodies or Met-CCL5 alleviates liver damage. These findings highlight CCL5 as a potential therapeutic target in ALF.
Hepatitis
CCL5 is prominently altered in hepatitis, including acute hepatitis and hepatitis caused by HBV and HCV infections.
The plant lectin concanavalin A (ConA) induces acute hepatitis by activating T cells and producing cytokines and chemokines. CCL5 levels increase post-ConA administration, and CCR5-deficient mice exhibit higher mortality and liver damage. Neutralizing CCL5 provides protection, suggesting the CCL5/CCR5 axis's significant role in immune-mediated liver injury. In hepatitis models induced by alpha-galactosylceramide, CCL5 deficiency worsens iNKT-mediated hepatitis by increasing hepatic neutrophil accumulation.
Studies have shown elevated CCL5 levels in HBV-infected patients. The expression of HBV's X gene in liver cells induces high CCL5 levels, correlating with disease progression. Certain genetic polymorphisms in CCL5 have been associated with HBV infection outcomes in specific ethnic cohorts. CCL5 contributes to immune cell recruitment in the liver, highlighting its role in HBV hepatitis.
HCV infection triggers liver damage through T cell-mediated immune responses and systemic oxidative stress. CCL5 levels correlate with HCV infection, promoting an antiviral response. Elevated CCL5 levels have been linked to GRP78 expression in TLR3-mediated antiviral efforts. CCL5 also activates HSCs, promoting fibrosis in HCV-infected livers. Increased CCL5 levels correlate with immune cell infiltration, demonstrating its significant role in liver cell injury due to HCV.
Alcoholic Liver Diseases (ALDs)
ALD, resulting from chronic alcohol consumption, leads to inflammation, fibrosis, and eventual liver failure. The role of CCL5 in ALD is complex and somewhat controversial. Some studies link elevated CCL5 levels with worse outcomes in alcoholic hepatitis, while others find no significant association. Genetic polymorphisms in the CCL5 promoter region have been linked to different risks of HCC development among ALD patients. This disparity suggests that the influence of CCL5 in ALD may vary across individuals, influenced by genetic and environmental factors.
Non-Alcoholic Fatty Liver Disease (NAFLD)
NAFLD, the most common liver disorder in developed countries, ranges from simple steatosis to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. CCL5 has been implicated in the progression of NAFLD. Elevated CCL5 levels are observed in NAFLD mouse models and patients with NASH. CCL5 contributes to hepatic inflammation and fibrosis by promoting the migration of lymphocytes and activation of hepatic stellate cells. Antagonists of CCL5, such as maraviroc and cenicriviroc, have shown efficacy in reducing hepatic steatosis and fibrosis, highlighting the potential for CCL5-targeted therapies in NAFLD.
Liver Fibrosis
Liver fibrosis results from sustained hepatocellular damage and chronic inflammation, leading to excessive extracellular matrix protein production. Elevated CCL5 levels are associated with advanced fibrosis. Studies using CCL5 antagonists like Met-CCL5 and mutated CCL5 proteins demonstrate reduced fibrosis and liver injury, suggesting CCL5 antagonism as a novel treatment option.
Hepatocellular Carcinoma (HCC)
The role of CCL5 in HCC has been extensively studied. CCL5 promotes tumor migration and invasion by activating various signaling pathways, including PI3K, MAPK, and Rho kinase. It also stimulates the migration and invasion of HCC cells through interactions with cancer-associated fibroblasts (CAFs) and bone marrow stromal cells. In mouse models, CCL5 deletion results in fewer and smaller tumors, indicating its role in HCC progression. CCL5 also contributes to tumor-associated macrophage recruitment and enhances liver inflammation in HCC models. These findings suggest that CCL5 could be a valuable target for HCC treatment, and ongoing studies are exploring therapeutic approaches to inhibit its activity.
Conclusion
CCL5 plays a central role in various liver diseases by modulating inflammatory responses, immune cell recruitment, and tissue damage. Its involvement in hepatic ischemia/reperfusion injury, acute liver failure, hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma underscores its potential as a therapeutic target. While CCL5-targeted therapies show promise in preclinical models, further research is needed to fully understand its mechanisms and optimize treatment strategies. Advances in this area could lead to more effective interventions for managing acute and chronic liver diseases.
References
- Chen L., et al. Functional roles of CCL5/RANTES in liver disease. Liver Research. 2020, 4 (1): 28-34.
- Mohs A., et al. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. Journal of Hepatology. 2017, 66 (4): 743-53.
- Soo H. M., et al. Expression of a full-length hepatitis C virus cDNA up-regulates the expression of CC chemokines MCP-1 and RANTES. Virology. 2002, 303 (2): 253-77.
- Lee C. M., et al. CC Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury. Scientific Reports. 2017, 7 (1): 3698.
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