Z Gastroenterol 2009; 47 - P4_27
DOI: 10.1055/s-0029-1191946

The chemokine receptor CXCR3 mediates NK cell recruitment and limits injury after toxic liver damage

M Moreno Zaldivar 1, M Berres 1, P Schmitz 1, C Offermanns 1, KR Karlmark 1, F Tacke 1, N Gassler 2, C Trautwein 1, HE Wasmuth 1
  • 1Medizinische Klinik III RWTH Universitätsklinikum Aachen
  • 2Institut für Pathologie, RWTH Universitätsklinikum Aachen

Aims: Chemokines play an important role in liver injury by modulation of immune cell recruitment to the damaged liver. NK and NKT cells are known to be important contributers to liver cell damage. Their recruitment is mediated by the CXCR3 ligands CXCL9 and CXCL10. But the role of CXCR3 has not yet been evaluated in acute liver injury.

Material and Methods: Acute liver injury was induced by injection of CCl4 (0.7mg/kg) in CXCR3-/- mice, wild-type littermates and after depletion of NK-cells in wild-type mice with an anti-asialo GM1 antibody (n=4–6). The degree of liver injury was assessed by liver histology (H&E staining), serum transaminases and TUNEL assay at days 1, 3 and 5 after injury. Recruitment of immune cells (NK cells, NKT cells) to the liver was assessed by FACS. CXCL9 and CXCL10 mRNA concentrations were analysed by real-time RT-PCR.

Results: Treatment of wild-type mice with CCl4 leads to an intrahepatic increase of the CXCR3 ligands CXCL9 and CXCL10 after 24h. CXCR3-/- mice display significantly elevated transaminase levels (P<0.002) and increased histological damage 24 hours after CCl4 compared to their wild-type littermates. This histological difference is also evident at days 3 and 5 after injury. FACS analysis shows significantly reduced numbers of NK and NKT cells after injury in CXCR3-/- mice at all time points (all P<0.05). The reduced number of NK cells is associated with a decrease in TUNEL positive cells. Importantly, the phenotype of CXCR3-/- mice is reproducible after NK-cell depletion in wild-type mice, indicating that NK cells and the chemokines that recruit them are directly associated with the degree of liver damage after CCl4.

Discussion: The increased vulnerability of CXCR3-/- mice after toxic injury is associated with decreased numbers of liver infiltrating NK-cells and reduced apoptosis. These results demonstrate an important role of CXCR3 in acute liver diseases and define a new pathway for therapeutic interventions.

CXCR3 - NK cells - acute liver injury - chemokine receptor