Chemokine scavenger receptor DARC displays gender-specific effects on intrahepatic expression of inflammatory chemokines in mice and fibrosis in man

Abstract

Introduction: Macrophage invasion of the liver modulates liver fibrosis in liver disease. MIP-1 the major chemokine of macrophage chemotaxis, plays a central role in macrophage recruitment. MIP-1 levels are genetically determined by variation in the gene encoding the duffy antigen receptor for chemokines (DARC). We hypothesised that the DARC receptor and its genetic variation affects the progression of liver fibrosis and studied the effect on acute and chronic liver injury in DARC deficient mice. Furthermore, we assessed the association of a common DARC variant with liver fibrosis in patients with chronic liver diseases. Patients and methods: Overall, 927 patients with chronic liver fibrosis were included in the study and staged for liver stiffness using transient elastography. Patients were classified as mild or advanced fibrosis using a TE cut-off of 9.5 kPa. Patients were genotyped for the common DARC SNP rs12075 (p.Asp42Gly) using Taqman assays. In addition, we challenged DARC deficient (KO) (n=5) and wild-type (WT) (n=3) mice with short-term and chronic CCl4 injections and compared the intrahepatic expression levels of pro-inflammatory chemokines (CCL2, CCL3, CCL5, CXCL9, CXCL12, IL6) between KO and WT mice. Results: Short-term CCl4 injection led to a marked increase in serum transaminase activities in both WT and KO mice but no differences in chemokine expression levels between WT and KO mice. However, gender-specific analysis revealed uniform increases in expression of all measured chemokines in female KO mice as compared to female WT mice, whereas there was no such difference in male mice. The largest difference in gene expression was detected for CCL5/RANTES (11.5±8.9 vs. 1.1±0.6; p=0.056) in female KO mice as compared to WT mice. Interestingly, when looking at patients we did not detect any association of the DARC SNP with liver fibrosis. Of note, when we analysed the subgroup of female patients we detected an association with the common allele and liver fibrosis (odds ratio=1.97; C.I.=0.998–3.888; p=0.048). Conclusion: We propose that genetic differences in the DARC receptor may account for gender differences in acute and/or chronic liver injury. However, the exact molecular mechanisms have to be clarified in further studies.