Document Detail


Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo.
MedLine Citation:
PMID:  16061736     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Niels R Veillard; Sabine Steffens; Graziano Pelli; B Lu; Brenda R Kwak; Craig Gerard; Israel F Charo; François Mach
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-08-01
Journal Detail:
Title:  Circulation     Volume:  112     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-09     Completed Date:  2006-02-14     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  870-8     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apolipoproteins E / deficiency
Atherosclerosis / genetics*,  pathology
Base Sequence
Crosses, Genetic
DNA Primers
Disease Models, Animal
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, CCR2
Receptors, CXCR3
Receptors, Chemokine / deficiency,  genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
HL52773/HL/NHLBI NIH HHS; HL63894/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apolipoproteins E; 0/Ccr2 protein, mouse; 0/Cxcr3 protein, mouse; 0/DNA Primers; 0/Receptors, CCR2; 0/Receptors, CXCR3; 0/Receptors, Chemokine

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