Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice

• DOI: 10.1002/hep.24764
• Publication Date: 2011-10-26T14:24:56Z
• Authors: Felix Heymann; Linda Hammerich; Dunja Storch; Matthias Bartneck; Sebastian Huss; Vanessa Rüsseler; Nikolaus Gassler; Sergio A. Lira; Tom Luedde; Christian Trautwein; Frank Tacke
• Keywords: CD4-Positive T-Lymphocytes; Liver Cirrhosis; Male; Mice, Knockout; 0303 health sciences; Neutrophils; Macrophages; Cell Differentiation; Immunity, Innate; Receptors, CCR8; Up-Regulation; 3. Good health; Killer Cells, Natural; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Phenotype; Liver; Cell Movement; Animals; Female

Chemokines critically control the infiltration of immune cells upon liver injury, thereby promoting hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte-derived dendritic cells (DCs) and T-helper cell (Th) subsets, but its role in liver diseases is currently unknown. To investigate the functional role of CCR8 in liver diseases,

ccr8

−/− and wild-type (WT) mice were subjected to chronic experimental injury models of carbon tetrachloride (CCl4) administration and surgical bile duct ligation (BDL). CCR8 was strongly up-regulated in the injured liver.

Ccr8

−/− mice displayed attenuated liver damage (e.g., ALT, histology, and 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 natural killer cells, whereas 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 but not for nonclassical 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 macrophage inflammatory protein 1-alpha (MIP-1α/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 critically mediates hepatic macrophage recruitment upon injury, which subsequently shapes the inflammatory response in the injured liver, affecting macrophage/DC and Th 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.