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Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in die interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fîbrosis that CCLS haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with dûs, we detected CdS mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCIi) or feeding on a methionine and choline-deficient (MCD) diet. In these models, Ccl5^sup -/-^ mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of GrU-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importandy, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors.
Introduction
Chronic liver diseases are a major cause of mortality and morbidity worldwide. Among chronic liver injuries, chronic hepatitis C virus infection and nonalcoholic steatohepatitis (NASH) are the most common entities in the United States and Europe leading to liver fibrosis and end-stage liver disease, including hepatocellular carcinoma (1). In these diseases, liver fibrosis is considered as the result of a chronic wound healing response to a continuous hepatocellular insult, which results in an inflammatory response within the liver and the subsequent activation of hepatic stellate cells, which produce an excess of extracellular matrix proteins (2, 3). Established liver fibrosis has long been considered as a static process, but this concept has recently been challenged by the finding that fibrosis and even cirrhosis are reversible in a considerable number of cases (4). These results have fuelled the enthusiasm that key pathways might be defined, whose modulation bears the potential to influence the natural history of chronic Hver diseases and...