Published Online
on August 1, 2005

A more recent version of this article appeared on August 9, 2005

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Submitted on January 14, 2004
Revised on April 20, 2005
Accepted on April 26, 2005

Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo

Niels R. Veillard PhD, Sabine Steffens PhD, Graziano Pelli , B. Lu MD, Brenda R. Kwak PhD, Craig Gerard MD, PhD, Israel F. Charo MD, PhD, and François Mach MD^*

From the Division of Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland (N.R.V., S.S., G.P., B.R.K., F.M.); Ina Sue Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, Mass (B.L., C.G.); Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco (I.F.C.); and Gladstone Institute of Cardiovascular Disease, San Francisco, Calif (I.F.C.).

^* To whom correspondence should be addressed. E-mail: francois.mach{at}medecine.unige.ch..

Background--Recruitment of mononuclear leukocytes within atherosclerotic lesions is a critical step in atherogenesis. Mice lacking the chemokine receptor CCR2, highly expressed on macrophages but also on T lymphocytes, show a striking reduction of atherosclerotic lesion formation. The chemokine receptor CXCR3 is a marker of activated T helper type 1 lymphocytes, the principal T lymphocyte type detected within atheroma. We investigated whether the deletion of both of these 2 important receptors expressed on the principal inflammatory cells present in atheroma would further affect atherogenesis in vivo.

Methods and Results--We crossed ApoE^-/- mice with either CCR2^-/- or CXCR3^- mice and crossed ApoE^-/- CCR2^-/- mice with the ApoE^-/- CXCR3^- mice to generate a triple knockout strain. Analysis of atherosclerosis development after 10 weeks of high-cholesterol diet revealed differential effects on early atherosclerotic lesions in the abdominal aorta and on advanced lesions in aortic roots. ApoE^-/- CXCR3^- mice, but not the triple knockout mice, displayed significantly reduced atherosclerotic lesion development within abdominal aortas compared with ApoE^-/- CCR2^-/- and ApoE^-/- mice. This reduction of lesion formation correlated with an upregulation of antiinflammatory molecules such as interleukin-10, interleukin-18BP, and endothelial nitric oxide synthase and with an increased number of regulatory T lymphocytes within atherosclerotic lesions. In contrast, lesion size development within the aortic roots was more enhanced in ApoE^-/- and ApoE^-/- CXCR3^- mice compared with ApoE^-/- CCR2^-/- and triple knockout mice.

Conclusions--Blocking chemokine signaling in vivo through deletion of the chemokine receptors CCR2 and CXCR3 has differential effects during atherogenesis. In addition, our results point to an important role of regulatory T lymphocytes during early atherogenesis.

Key words: atherogenesis • chemokine • immunology • inflammation • leukocytes

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