The presence of leukocyte CC-chemokine receptor 2 in CCR2 knockout mice promotes atherogenesis

AbstractObjective:To selectively determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in atherogenesis.Methods and results:Bone marrow progenitor cells harvested from CCR2(+/+) mice were transplanted into irradiated CCR2(−/−) mice, representing the whole-body absence of CCR2 except in leukocytes. Transplantation of CCR2(−/−) bone marrow into CCR2(−/−) mice served as control. Eight weeks after bone marrow transplantation, the diet of regular chow was switched to a high-cholesterol diet for another 10 weeks in order to induce atherosclerosis. No significant differences in serum cholesterol and triglyceride levels were observed between the two groups. However, the mean cross-sectional aortic root lesion area of CCR2(+/+)→CCR2(−/−) mice amounted up to 12.28±3.28×104 μm2, compared with only 3.08±0.74×104 μm2 observed in the CCR2(−/−)→CCR2(−/−) group. Thus, the presence of CCR2 exclusively on leukocytes induces a fourfold increase in aortic lesion area. This extent of lesion development was comparable to C57Bl/6 mice receiving CCR2(+/+) bone marrow (10.08±3.30×104 μm2).Conclusion:These results point at a dominant role of leukocyte CCR2 in atherogenesis, implying that CCR2 from nonleukocyte sources, like endothelial cells or smooth muscle cells, is less critical in the initiation of atherosclerosis. Pharmacological inhibition of leukocyte CCR2 function might be a promising strategy to prevent atherosclerosis