Functional role of CCL5/RANTES for HCC progression during chronic liver disease

Abstract

BACKGROUND & AIMS: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to HCC development. METHODS: CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMO(Δhepa)/CCL5(-/-) animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24 hours or 8 weeks. RESULTS: In CLD patients CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2(-/-) and NEMO(Δhepa) model. CCL5 deletion in NEMO(Δhepa) mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45(+)/Ly6G(+) granulocytes, CD45(+)/CD11b(+)/Gr1.1(+)/F4/80(+) pro-inflammatory monocytes, CD4(+) and CD8(+) T cells were decreased. One year old NEMO(Δhepa)/CCL5(-/-) mice displayed smaller and less malignant tumours, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as main source of CCL5, while CCL5 deficiency did not sensitise NEMO(Δhepa) hepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8 weeks ameliorated liver disease progression. CONCLUSION: We identified an important role of CCL5 in human and functionally in mice for disease progression and especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD. (247/250).