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Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice.

Wan, Wuzhou; Lim, Jean K; Lionakis, Michail S; Rivollier, Aymeric; McDermott, David H; Kelsall, Brian L; Farber, Joshua M; Murphy, Philip M.
Circ Res; 109(4): 374-81, 2011 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-21680896
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:

Our objective was 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(+)Ly6C(high) 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.