Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis

Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors 1 , 2 . In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques 3 , 4 , in arteries of primates on a hypercholesterolaemic diet 5 and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids 5 , 6 . To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 ( ref. 7 ), and crossed them with apolipoprotein (apo) E-null mice 8 , 9 , 10 which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE −/− mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.