Met-CCL5 modifies monocyte subpopulations during liver fibrosis regression.

Fibrosis or scarring of the liver parenchyma is a mainstay of chronic liver diseases and is associated with increased morbidity and mortality. Since complete scarring of the liver develops over several decades, therapeutic intervention with the aim of ameliorating fibrosis is of great clinical interest. In a recent study, we could identify the chemokine receptor antagonist Met-CCL5 as a potential compound to inhibit fibrosis progression and accelerate its regression. In the current study we characterized immune changes during fibrosis regression associated with the treatment with the CCL5 (RANTES) chemokine receptor antagonist Met-CCL5 in an established mouse model of chronic liver damage. Met-CCL5 or PBS was given after fibrosis induction (8 weeks of CCl(4)) and mice were sacrificed three and seven days after peak fibrosis. Mouse livers were analyzed for immune cell infiltration and cytokine gene expression. The results show that overall monocyte recruitment was not affected by Met-CCL5, but there was a significant shift to a pro-inflammatory Gr1+ monocyte population in the livers of mice treated with Met-CCL5. These monocytes were mostly iNOS +, a phenomenon which was also evident when analyzing the overall gene expression profiles in the livers. Since a shift in monocyte subpopulations has recently been identified to contribute to fibrosis regression, our results help explaining the efficacy of CCL5 chemokine antagonism as a novel treatment option for fibrotic liver diseases.