Abstract
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 receptors1,2. 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 plaques3,4, in arteries of primates on a hypercholesterolaemic diet5 and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids5,6. 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 mice8,9,10 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.
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References
Cocchi, F. et al. Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1995).
Choe, H. et al. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135–1148 (1996).
Nelken, N. A., Coughlin, S. R., Gordon, D. & Wilcox, J. N. Monocyte chemoattractant protein-1 in human atheromatous plaques. J. Clin. Invest. 88, 1121–1127 (1991).
Yiä-Herttuala, S. et al. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc. Natl Acad. Sci. USA 88, 5252–5256 (1991).
Yu, X. et al. Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc. Natl Acad. Sci. USA 89, 6953–6957 (1992).
Cushing, S. D. et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl Acad. Sci. USA 87, 5134–5138 (1990).
Boring, L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552–2561 (1997).
Plump, A. S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombinant in ES cells. Cell 71, 343–353 (1992).
Zhang, S. H., Reddick, R. L., Piedrahita, J. A. & Maeda, N. Spontaneous hypercholsterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468–471 (1992).
Plump, A. S., Scott, C. J. & Breslow, J. L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc. Natl Acad. Sci. USA 91, 9607–9611 (1994).
Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L. & Ross, R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).
Kraal, G., Rep, M. & Janse, M. Macrophages in T and B cell compartments and other tissue macrophages recognized by monoclonal antibody MOMA-2. An immunohistochemical study. Scand. J. Immunol. 26, 653–661 (1987).
Gupta, S. et al. IFN-γ potentiates atherosclerosis in apoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).
Duverger, N. et al. Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. Science 273, 966–968 (1996).
Suzuki, H. et al. Arole for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386, 292–296 (1997).
Purcell-Huynh, D. A. et al. Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. J. Clin. Invest. 95, 2246–2257 (1995).
Véniant, M. M. et al. Susceptibility to atherosclerosis in mice expressing exclusively apolipoprotein B48 or apolipoprotein B100. J. Clin. Invest. 100, 180–188 (1997).
Acknowledgements
We thank D. Sanan, D. Newland and L. Jensen for help with tissue preparation and staining; D. Dichek for advice on statistical analysis; J. C. W. Carroll, N. C. Shea and S. Gonzales for figurepreparation; J. Ernst for assistance with fluorescent microscopy; G. Howard and S. Ordway for editorial expertise; and A. Chen for manuscript preparation. We also thank R. Pitas, R. Farese and K.Weisgraber for careful readings of the manuscript. This work was supported in part by a grant from the NIH to I.F.C.
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Boring, L., Gosling, J., Cleary, M. et al. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998). https://doi.org/10.1038/29788
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DOI: https://doi.org/10.1038/29788
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