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) gamma, and targeting the PPARgamma 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 PPARgamma 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.