Duffy antigen receptor for chemokines (DARC) on non‐hematopoietic tissues curbs atherosclerosis in apolipoprotein E‐deficient mice

Abstract

The Duffy antigen receptor for chemokines (DARC) is a non-signaling, promiscuous chemokine receptor expressed on red blood cells (RBCs) and high endothelial venules (HEVs). The function of RBC DARC and HEV DARC in inflammatory disease is not well understood. In order to examine the role of DARC in atherosclerosis, we backcrossed apolipoprotein E knockout (apoE−/−) mice with DARC knockout (DARC−/−) mice to create double knockout (apoE−/−/DARC−/−) mice. apoE−/−/DARC−/− and apoE−/− mice were fed a Western diet for 12 weeks. Aortas were then stained with Oil Red O and percent aortic area with atherosclerotic lesion was quantified. apoE−/−/DARC−/− and apoE−/− mice developed lesions on 6.1 ± 2.7% and 4.2 ± 1.4% (average ± SEM, p<0.05) of their aortas, respectively. To differentiate between RBC DARC and HEV DARC, we performed the same analysis on apoE−/− mice and apoE−/−/DARC−/− mice reconstituted with either apoE−/− or apoE−/−/DARC−/− bone marrow. DARC expression on non-hematopoietic cells protected mice from atherosclerosis to the same extent as complete DARC expression (4.6 ± 1.0% and 4.9 ± 1.1%, respectively, p>0.05). By contrast, apoE−/−/DARC−/− receiving either apoE−/− (8.3 ± 1.6%) or apoE−/−/DARC−/− (7.8 ± 1.7%) bone marrow exhibited a 1.5-fold increase in lesion areas compared to mice expressing DARC on non-hematopoietic cells (p<0.05 for groups expressing DARC on non-hematopoietic tissue versus those deficient in DARC on non-hematopoietic tissue). We conclude that HEV DARC, but not RBC DARC, is involved in curbing atherosclerosis. This work was supported by NIH HL 58108 and the American Heart Association.