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


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.
Veillard
Niels R
NR
Division of Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland.
Steffens
Sabine
S
Pelli
Graziano
G
Lu
B
B
Kwak
Brenda R
BR
Gerard
Craig
C
Charo
Israel F
IF
Mach
François
F
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; C515188:Cxcr3 protein, mouse; D017931:DNA Primers; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine