CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation

Chemokines such as CXCL10 promote hepatic inflammation in chronic or acute liver injury through recruitment of leukocytes to the liver parenchyma The CXCL10 receptor CXCR3 which is expressed on a subset of leukocytes plays an important part in Th1-dependent inflammatory responses Here we investigated the role of CXCL10 in chemically induced liver fibrosis We used carbon tetrachloride (CCI4) to trigger chronic liver damage in wildtype C57BL/6 and CXCL10-deficient mice Fibrosis severity was assessed by Sinus Red staining and intrahepatic leukocyte subsets were investigated by immunohistochemistry We have further analyzed hepatic stellate cell (HSC) distribution and activation and investigated the effect of CXCL10 on HSC motility and proliferation In order to demonstrate a possible therapeutic intervention strategy we have examined the anti-fibrotic potential of a neutralizing anti-CXCL10 antibody Upon CCI4 administration CXCL10-deficient mice showed massively reduced liver fibrosis when compared to wildtype mice CXCL10-deficient mice had less B- and T lymphocyte and dendritic cell infiltrations within the liver and the number and activity of HSCs was reduced In contrast natural killer (NK) cells were more abundant in CXCL10-deficient mice and granzyme B expression was increased in areas with high numbers of NK cells Further detailed analysis revealed that HSCs express CXCR3 respond to CXCL10 and secrete CXCL10 when stimulated with IFN-gamma Blockade of CXCL10 with a neutralizing antibody exhibited a significant anti-fibrotic effect Our data suggest that CXCL10 is a pro-fibrotic factor which participates in a crosstalk between hepatocytes HSCs and Immune cells NK cells seem to play an important role in controlling HSC activity and fibrosis CXCL10 blockade may constitute a possible therapeutic intervention for hepatic fibrosis (c) 2010 Elsevier Ltd All rights reserved