Genetic Deletion of Chemokine Receptor Ccr6 Decreases Atherogenesis in ApoE-Deficient Mice
Rationale: The chemokine receptor Ccr6 is a G-protein–coupled receptor expressed on various types of leukocytes identified in mouse atherosclerotic lesions. Recent evidence suggests that both CCR6 and its ligand CCL20 are also present in human atheroma; however, their functional roles in atherogenesis remain undefined.
Objective: To delineate the role of Ccr6 in atherogenesis 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. Aortic lesion area in Ccr6−/−ApoE−/− mice was ≈40% and ≈30% smaller than in Ccr6+/+ApoE−/− mice at 16 and 24 weeks of age, respectively. Transplantation of bone marrow from Ccr6−/− mice into ApoE−/− mice resulted in ≈40% less atherosclerotic lesion area than for bone marrow from Ccr6+/+ mice; lesions in Ccr6−/−ApoE−/− mice had 44% less macrophage content than lesions in Ccr6+/+ApoE−/− mice. Ccr6 was expressed on a subset of primary mouse monocytes. Accordingly, 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 circulating blood of Ccr6−/−ApoE−/− mice, mainly because of fewer CD11b+Ly6Chigh inflammatory monocytes.
Conclusions: Ccr6 promotes atherosclerosis in ApoE-deficient mice, which may be due in part to Ccr6 support of normal monocyte levels in blood, as well as direct Ccr6-dependent monocyte migration.
- Received February 14, 2011.
- Revision received June 3, 2011.
- Accepted June 7, 2011.
- © 2011 American Heart Association, Inc.