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(Circulation. 2007;116:1801-1811.)
© 2007 American Heart Association, Inc.

Vascular Medicine

CXCR6 Promotes Atherosclerosis by Supporting T-Cell Homing, Interferon- Production, and Macrophage Accumulation in the Aortic Wall

Elena Galkina, PhD; Brian L. Harry, BS; Andreas Ludwig, PhD; Elisa A. Liehn, MD; John M. Sanders, BS; Anthony Bruce, MS; Christian Weber, MD; Klaus Ley, MD

From the Departments of Biomedical Engineering (E.G., B.L.H., K.L.), Molecular Physiology and Biological Physics (K.L.), and Robert M. Berne Cardiovascular Research Center (E.G., A.B., J.M.S., K.L.), University of Virginia, Health Sciences Center, Charlottesville; and Institute of Molecular Cardiovascular Research, Aachen, Germany (A.L., E.A.L., C.W.).

Correspondence to Elena Galkina, PhD, Robert M. Berne Cardiovascular Research Center, University of Virginia, PO Box 801394, Charlottesville, VA 22908. E-mail evg7c{at}virginia.edu

Received November 27, 2006; accepted August 3, 2007.

Background— T lymphocytes are thought to be important in atherosclerosis, but very little is known about the mechanisms of lymphocyte recruitment into atherosclerosis-prone aortas. In this study we tested the hypothesis that CXCR6, a chemokine receptor that is expressed on a subset of CD4⁺ T helper 1 cells and natural killer T cells, is involved in lymphocyte homing into the aortic wall and modulates the development and progression of atherosclerosis.

Methods and Results— To investigate the role of CXCR6 in the development and progression of atherosclerosis, we bred CXCR6-deficient (CXCR6^GFP/GFP) mice with apolipoprotein E–deficient (ApoE^–/–) mice. We found that CXCR6^GFP/GFP/ApoE^–/– mice fed a Western diet for 17 weeks or a chow diet for 56 weeks had decreased atherosclerosis compared with ApoE^–/– controls. Flow cytometry analysis of the aortas from CXCR6^GFP/GFP/ApoE^–/– mice showed that the reduction of atherosclerosis was accompanied by a decreased percentage of CXCR6⁺ T cells within the aortas. Short-term homing experiments demonstrated that CXCR6 is involved in the recruitment of CXCR6⁺ leukocytes into the atherosclerosis-prone aortic wall. The reduced percentage of CXCR6⁺ T cells within the aortas resulted in significantly diminished production of interferon- and reduction of CD11b⁺/CD68⁺ macrophages in the aorta.

Conclusions— These data provide evidence for a proatherosclerotic role of CXCR6. Absence of CXCR6 alters the recruitment of CXCR6⁺ leukocytes and modulates the local immune response within the aortic wall.

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