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
