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 may modulate liver fibrosis in acute and chronic liver disease. MIP-1, the major chemokine of macrophage chemotaxis, plays a central role in macrophage recruitment. Recently it was shown that MIP-1 serum levels are genetically determined by variation in the DARC gene encoding the duffy antigen receptor for chemokines. We hypothesised that this receptor and its genetic variation modify the progression of liver fibrosis and studied the effects of acute and chronic liver injury in DARC deficient mice. We also tested for association of a common DARC variant with liver fibrosis in a human population of patients with chronic liver diseases who were phenotyped non-invasively by elastography. Patients and methods:Overall, we determined liver stiffness in 927 patients with chronic liver fibrosis using transient elastography (TE, Fibroscan). Patients were classified as presenting with mild or advanced fibrosis using a TE cut-off of 9.5 kPa. Patients were genotyped for the common DARC polymorphism rs12075 (p.Asp42Gly) using Taqman assays. In addition, we challenged DARC deficient and wild-type mice with CCl4 injections (24h and 6 weeks, respectively) and compared intrahepatic steady-state mRNA levels of pro-inflammatory chemokines (CCL2, CCL3, CCL5, CXCL9, CXCL12, IL6) and collagen 1a2 between DARC-deficient mice and controls. Results: Short-term CCl4 injection led to a marked increase in serum transaminase activities and increased intrahepatic levels of CCL2, CCL5, and IL6. Gender-specific analysis revealed that male knockout mice showed a significant increase in intrahepatic expression of Ccl2 (2.88 ± 0.67 vs. 1.03 ± 0.96; p=0.001), Ccl5 (1.95 ± 0.77 vs. 0.96 ± 1.00; p=0.005), Cxcl9 (0.85 ± 0.59 vs. 0.38 ± 0.16; p=0.044) and Cxcl12 (4.10 ± 2.31 vs. 0.86 ± 1.05; p=0.003) in comparison to controls while ALT levels were highest in the latter. Interestingly, long-term injection did not reveal any differences in ALT levels, chemokine or collagen expression; there was no difference in hepatic collagen contents either. Overall, we did not detect any association of the DARC variant with liver fibrosis in patients with chronic liver diseases. However, in the group of female patients, we detected an association between the common DARC allele and liver fibrosis (odds ratio = 1.97; 95% CI = 0.998 - 3.888; p = 0.048).¶ Conclusion:¶ We propose that genetic variation of the DARC receptor may account for gender differences in acute and chronic liver injury in mice and humans. The exact mechanisms have to be clarified in further functional studies.