The chemokine receptor CCR8 critically controls hepatic macrophage migration and differentiation in murine liver fibrosis

Aims: Chemokines are important regulators of immune cell infiltration upon liver injury, thereby controlling hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte-derived dendritic cells (DCs) and T helper cell subsets, but its role in liver diseases is currently unknown.

Methods: ccr8-/- and wildtype (wt) mice were subjected to chronic experimental hepatic injury models (carbon tetrachloride (CCl4), surgical bile duct ligation).

Results: Ccr8-/- mice displayed attenuated liver damage (ALT, histology, TUNEL) compared to wt mice, and were also protected from liver fibrosis in two independent injury models. Flow cytometry revealed reduced infiltrates of liver macrophages, neutrophils and NK cells, while hepatic CD4+ T cells increased. The main CCR8-expressing cells in the liver were hepatic macrophages, and CCR8 was functionally necessary for CCL1-directed migration of inflammatory monocytes into the liver. Moreover, the phenotype of liver macrophages from injured ccr8-/- animals was altered with increased expression of DC-markers and enhanced expression of T-cell attracting chemokine MIP1-alpha (CCL3). Correspondingly, hepatic CD4+ T-cells showed increased Th1 polarization and reduced Th2-cells in CCR8-deficient animals. Liver fibrosis progression, but also subsequent T-cell alterations could be restored by adoptively transferring CCR8-expressing monocytes/macrophages into ccr8-/- mice during experimental injury.

Conclusions: CCR8 is a critical mediator of hepatic macrophage infiltration upon injury, which subsequently shapes the inflammatory response in injured liver affecting macrophage/DC and T-helper cell differentiation. CCR8 deficiency protects the liver against injury, ameliorating initial inflammatory responses and hepatic fibrogenesis. Inhibition of CCR8 or its ligand CCL1 might represent a successful therapeutic target to limit liver inflammation and fibrosis progression.

Chemokine - Leberfibrose - Makrophagen - Mausmodelle - Monozyten