Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice (117.2)

Abstract

Abstract Background—The chemokine receptor CCR6 and its ligand CCL20 are both expressed in human atheroma; however, their functional roles in atherogenesis remain undefined. Here, we addressed this question in the apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Methods and Results—Both Ccr6 and Ccl20 are expressed in atherosclerotic aorta from ApoE-/- mice. Atherosclerotic lesion area in the aorta in Ccr6-/-ApoE-/- mice was ~40% and ~30% smaller than in Ccr6+/+ApoE-/- mice at 16 and 24 weeks of age, respectively. In addition, lesions of Ccr6-/-ApoE-/- mice had 44% less macrophage content compared to Ccr6+/+ApoE-/- mice. Since monocytes are the source of lesional macrophages, we tested whether monocytes express Ccr6 and the effect of Ccr6 deletion on monocyte function. We found that Ccr6 was expressed on a subset of primary mouse monocytes and on the mouse monocyte/macrophage cell line RAW 264.7. The receptor was functional, as defined by Ccl20-induced chemotaxis of primary monocytes from wild type but not Ccr6-/- mice; moreover, Ccl20 induced monocytosis in ApoE-/- mice in vivo. Consistent with this, we observed 30% fewer monocytes in the circulating blood of Ccr6-/-ApoE-/- mice, mainly due to fewer CD11b+Ly6Chigh inflammatory monocytes. Conclusions—We conclude that Ccr6 promotes atherosclerosis in ApoE-deficient mice. This may be due in part to Ccr6 support of normal monocyte levels in blood in the model, as well as direct Ccr6-dependent monocyte migration.