Role of CCL5 in a model of chronic liver injury and tumorigenesis

• Die Rolle von CCL5 während der chronischen Leberentzündung und Tumorigenese

Mohs, Antje; Elling, Lothar (Thesis advisor); Trautwein, Christian (Thesis advisor); Pradel, Gabriele (Thesis advisor)

Aachen (2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019

Abstract

Background Aims: Chronic hepatocyte injury with a continuous inflammatory response is the basis for liver disease progression triggering liver fibrosis as well as malignant transformation leading to hepatocellular carcinoma (HCC). Immune cells play a central role in this multifactorial process. Therefore, in the present study we aimed to investigate the role of CCL5 in humans, but also mechanistically in a murine model of chronic liver inflammation leading to HCC development. Methods: The expression of CCL5 and its receptors was examined in a well-defined patient co-hort with chronic liver disease. The NEMOΔhepa model of chronic liver disease in mice was used to investigate the role of CCL5 (NEMOΔhepa/CCL5-/- mice) for disease progression. Additionally, bone marrow transplantation (BMT) experiments and interventional studies using Evasin-4 - a chemokine binding protein - were performed to evaluate the impact of pharmacological intervention for disease progression. Results: In humans CCL5 expression increases with the grad of liver fibrosis and is associated with a significant overexpression of CCR5 - an observation that has been confirmed in the murine NEMOΔhepa model of chronic liver disease. CCL5 deletion in NEMOΔhepa mice improved liver injury, accompanied by decreased apoptosis and compensatory proliferation. In addition, the inflammatory milieu was reduced and showed a diminished immune cell infiltration, especially pro-inflammatory monocytes, Ly6G+ granulocytes, CD4+ and CD8+ T cells. Time-dependent analysis revealed a decrease in fibrosis progression and tumor development in NEMOΔhepa/CCL5-/- mice. Bone marrow transplantation experiments identified hematopoietic cells as the relevant source of CCL5 production. Finally, therapeutic intervention with Evasin-4 over a period of 8 weeks significantly ameliorated liver disease progression. Conclusion: Our present analysis identifies the important role of CCL5 in men and functionally in mice for disease progression and especially HCC development. A novel approach to inhibit CCL5 in vivo seems also encouraging treatment option for humans.