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(Circulation. 2006;114:807-819.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Oxidized Lipid-Driven Chemokine Receptor Switch, CCR2 to CX3CR1, Mediates Adhesion of Human Macrophages to Coronary Artery Smooth Muscle Cells Through a Peroxisome Proliferator-Activated Receptor –Dependent Pathway

Jana Barlic, PhD; Yuan Zhang; John F. Foley, PhD; Philip M. Murphy, MD

From the Molecular Signaling Section (J.B., Y.Z., P.M.M.) and Inflammation Biology Section (J.F.F.), Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Correspondence to Philip M. Murphy, MD, 9000 Rockville Pike, Bldg 10, Room 11N113, NIH, Bethesda, MD 20892. E-mail pmm{at}nih.gov

Received November 18, 2005; revision received June 14, 2006; accepted June 19, 2006.

Background— Recent genetic data in mouse and humans suggest that the chemokine receptors CCR2 and CX3CR1 are involved in atherogenesis; however, detailed molecular and cellular mechanisms have not been fully delineated.

Methods and Results— Here, we show that oxidized linoleic acid metabolites, which are components of oxidized LDL found in large amounts in atherosclerotic plaque, were able to specifically induce differentiation of human monocytes to macrophages with decreased expression of CCR2, confirming a previous report, and increased expression of CX3CR1. These macrophages acquired the ability to adhere to coronary artery smooth muscle cells. The adhesion was mediated directly and predominantly by CX3CR1. Reciprocal effects of these lipids on CCR2 and CX3CR1 expression were mediated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR) , and targeting the PPAR gene with sRNAi dramatically reduced macrophage adhesion to coronary artery smooth muscle cells.

Conclusions— These data suggest that in atherogenesis oxidized lipid-driven activation of macrophage PPAR in the intima may result in a proadhesive chemokine receptor switch–CCR2 off, CX3CR1 on–causing cessation of CCR2-dependent migration and activation of CX3CR1-dependent retention mechanisms, which together promote macrophage accumulation in vessel wall. Our results may explain at the molecular and cell biology levels the genetic link between CX3CR1 and atherosclerosis. Moreover, they identify macrophage binding to coronary artery smooth muscle cells as the first primary cell setting in which CX3CR1 functions as the major adhesion system.

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