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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:243.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

CX₃CR1 Deficiency Impairs Dendritic Cell Accumulation in Arterial Intima and Reduces Atherosclerotic Burden

Peng Liu; Yen-Rei A. Yu; Jessica A. Spencer; Ashley E. Johnson; Christopher T. Vallanat; Alan M. Fong; Cam Patterson; Dhavalkumar D. Patel

From the Thurston Arthritis Research Center and Department of Medicine (P.L., Y.-R.A.Y., J.A.S., A.E.J., C.T.V., A.M.F., D.D.P.) and the Carolina Cardiovascular Biology Center and Division of Cardiology (C.P.), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC; and the Novartis Institutes for BioMedical Research (D.D.P.), Basel, Switzerland.

Correspondence to Dhavalkumar D. Patel, University of North Carolina at Chapel Hill, CB# 7280, 3300 Thurston Building, Chapel Hill, NC 27599-7280. E-mail ddpatel{at}med.unc.edu; or Novartis Institutes of Biomedical Research, WSJ 386.11.25, CH-4002, Basel, Switzerland. E-mail dhavalkumar.patel@novartis.com

Abstract

Objective— Dendritic cells (DCs) have recently been found in atherosclerosis-predisposed regions of arteries and have been proposed to be causal in atherosclerosis. The chemokine receptor CX₃CR1 is associated with arterial injury and atherosclerosis. We sought to determine whether a link exists between arterial DC accumulation, CX₃CR1, and atherosclerosis.

Methods and Results— Mouse aortas were isolated and subjected to en face immunofluorescence analysis. We found that DCs were located predominantly in the intimal regions of arterial branch points and curvatures. Consistent with the increased accumulation of intimal DCs in aged and ApoE^–/– aortas compared with young WT aortas (P=0.004 and 0.05, respectively), the incidence of atherosclerosis was 88.9% for aged WT and 100% for ApoE^–/– mice compared with 0% for young WT mice. CX₃CR1 was expressed on intimal DCs and DC numbers were decreased in CX₃CR1-deficient aortas of young, aged, and ApoE^–/– mice (P=0.0008, 0.013, and 0.0099). The reduced DC accumulation in CX₃CR1-deficiency was also correlated with decreased atherosclerosis in these animals.

Conclusions— The accumulation of intimal DC increases in aged and ApoE^–/– aortas and correlates with the generation of atherosclerosis. CX₃CR1-deficiency impairs the accumulation of DC in the aortic wall and markedly reduces the atherosclerotic burden.

Dendritic cells (DCs) and the chemokine receptor CX₃CR1 have been implicated in the pathogenesis of atherosclerosis. In mouse aortas, CX₃CR1 was expressed on intimal DCs that increased abundance in aged and ApoE^–/– aortas. CX₃CR1 deficiency impairs the accumulation of DCs in the aortic wall and reduces the atherosclerotic burden.

Key Words: atherosclerosis • chemokine and chemokine receptor • dendritic cells • macrophages • animal models of human disease

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