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(Circulation. 2008;117:1642-1648.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2^–/– Mice

Evidence for Independent Chemokine Functions in Atherogenesis

Noah Saederup, PhD; Liana Chan, BA; Sergio A. Lira, MD, PhD; Israel F. Charo, PhD, MD

From the Gladstone Institute of Cardiovascular Disease (N.S., L.C., I.F.C.), San Francisco, Calif; Immunobiology Institute (S.A.L.), Mount Sinai School of Medicine, New York, NY; and Cardiovascular Research Institute (I.F.C.), Department of Medicine, University of California, San Francisco, Calif.

Correspondence to Israel F. Charo, MD, PhD, Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, CA, 94158. E-mail icharo{at}gladstone.ucsf.edu

Received October 3, 2007; accepted October 31, 2007.

Background— Monocyte-derived foam cells are the hallmark of early atherosclerosis, and recent evidence indicates that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Genetic deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2), fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1, markedly reduce atherosclerotic lesion size in murine models of atherosclerosis. The aim of this study was to determine whether these 2 chemokines act independently or redundantly in promoting atherogenesis.

Methods and Results— We crossed CX3CL1^–/–ApoE^–/– and CCR2^–/–ApoE^–/– mice to create CX3CL1^–/–CCR2^–/–ApoE^–/– triple knockouts and performed a 4-arm atherosclerosis study. Here, we report that deletion of CX3CL1 in CCR2^–/– mice dramatically reduced macrophage accumulation in the artery wall and the subsequent development of atherosclerosis. Deletion of CX3CL1 did not reduce the number of circulating monocytes in either "wild-type" ApoE^–/– mice or CCR2^–/–ApoE^–/– mice, which suggests a role for CX3CL1 in the direct recruitment and/or capture of CCR2-deficient monocytes.

Conclusions— These data provide the first in vivo evidence for independent roles for CCR2 and CX3CL1 in macrophage accumulation and atherosclerotic lesion formation and suggest that successful therapeutic strategies may need to target multiple chemokines or chemokine receptors.

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Clinical Summaries
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