Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo

被引:117
作者
Veillard, NR
Steffens, S
Pelli, G
Lu, B
Kwak, BR
Gerard, C
Charo, IF
Mach, F
机构
[1] Univ Hosp Geneva, Div Cardiol, Dept Med, Fdn Med Res, CH-1211 Geneva, Switzerland
[2] Childrens Hosp, Ina Sue Perlmutter Lab, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA 02115 USA
[4] Univ Calif San Francisco, Dept Med, Inst Cardiovasc Res, San Francisco, CA 94143 USA
[5] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA
关键词
atherogenesis; chemokine; immunology; inflammation; leukocytes;
D O I
10.1161/CIRCULATIONAHA.104.520718
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:870 / 878
页数:9
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