Home LiteratureArticle Details
PMID: 18165355 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis.

Circulation ·Vol. 117 ·No. 13 ·2008-04-01 ·Pages 1642-8

Saederup N, Chan L, Lira SA, Charo IF

Abstract

Monocyte-derived foam cells are the hallmark of early atherosclerosis, and recent evidence indicates that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Genetic deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2), fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1, markedly reduce atherosclerotic lesion size in murine models of atherosclerosis. The aim of this study was to determine whether these 2 chemokines act independently or redundantly in promoting atherogenesis. We crossed CX3CL1(-/-)ApoE(-/-) and CCR2(-/-)ApoE(-/-) mice to create CX3CL1(-/-)CCR2(-/-)ApoE(-/-) triple knockouts and performed a 4-arm atherosclerosis study. Here, we report that deletion of CX3CL1 in CCR2(-/-) mice dramatically reduced macrophage accumulation in the artery wall and the subsequent development of atherosclerosis. Deletion of CX3CL1 did not reduce the number of circulating monocytes in either "wild-type" ApoE(-/-) mice or CCR2(-/-)ApoE(-/-) mice, which suggests a role for CX3CL1 in the direct recruitment and/or capture of CCR2-deficient monocytes. These data provide the first in vivo evidence for independent roles for CCR2 and CX3CL1 in macrophage accumulation and atherosclerotic lesion formation and suggest that successful therapeutic strategies may need to target multiple chemokines or chemokine receptors.

MeSH Terms
Animals Arteriosclerosis/etiology,genetics,pathology Cell Migration Inhibition Cell Movement/physiology Chemokine CX3CL1/deficiency,genetics,physiology Chemokines/physiology Female Macrophages/pathology Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, CCR2/deficiency,genetics,physiology
Chemicals
Ccr2 protein, mouse Chemokine CX3CL1 Chemokines Receptors, CCR2
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Saederup Noah
Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, CA 94158, USA.
Chan Liana
Lira Sergio A
Charo Israel F
References (29)
29 references, click to expand
  1. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis.
    J Clin Invest. 2003 Feb;111(3):333-40 PMID: 12569158
  2. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice.
    Circulation. 2003 Feb 25;107(7):1009-16 PMID: 12600915
  3. Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age.
    J Mol Med (Berl). 2003 Jun;81(6):363-7 PMID: 12719858
  4. Blood monocytes consist of two principal subsets with distinct migratory properties.
    Immunity. 2003 Jul;19(1):71-82 PMID: 12871640
  5. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice.
    Circ Res. 2004 Feb 6;94(2):253-61 PMID: 14656931
  6. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells.
    Proc Natl Acad Sci U S A. 1990 Jul;87(13):5134-8 PMID: 1695010
  7. Cell biology of atherosclerosis.
    Annu Rev Physiol. 1995;57:791-804 PMID: 7778883
  8. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice.
    J Clin Invest. 1997 Nov 15;100(10):2552-61 PMID: 9366570
  9. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice.
    J Clin Invest. 1998 Jan 15;101(2):353-63 PMID: 9435307
  10. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis.
    Nature. 1998 Aug 27;394(6696):894-7 PMID: 9732872
  11. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.
    Mol Cell. 1998 Aug;2(2):275-81 PMID: 9734366
  12. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B.
    J Clin Invest. 1999 Mar;103(6):773-8 PMID: 10079097
  13. Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice.
    Atherosclerosis. 1999 Mar;143(1):205-11 PMID: 10208497
  14. Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root.
    Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17795-800 PMID: 15596719
  15. Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo.
    Circulation. 2005 Aug 9;112(6):870-8 PMID: 16061736
  16. CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study.
    Circulation. 2005 Aug 23;112(8):1113-20 PMID: 16116069
  17. Monocyte and macrophage heterogeneity.
    Nat Rev Immunol. 2005 Dec;5(12):953-64 PMID: 16322748
  18. The many roles of chemokines and chemokine receptors in inflammation.
    N Engl J Med. 2006 Feb 9;354(6):610-21 PMID: 16467548
  19. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.
    Nat Immunol. 2006 Mar;7(3):311-7 PMID: 16462739
  20. The immune response in atherosclerosis: a double-edged sword.
    Nat Rev Immunol. 2006 Jul;6(7):508-19 PMID: 16778830
  21. Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway.
    Circulation. 2006 Aug 22;114(8):807-19 PMID: 16908772
  22. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.
    J Clin Invest. 2007 Jan;117(1):185-94 PMID: 17200718
  23. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.
    Blood. 2001 Apr 1;97(7):1925-8 PMID: 11264153
  24. Generation and analysis of mice lacking the chemokine fractalkine.
    Mol Cell Biol. 2001 May;21(9):3159-65 PMID: 11287620
  25. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients.
    Atherosclerosis. 2001 Sep;158(1):233-9 PMID: 11500196
  26. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.
    Circ Res. 2001 Aug 31;89(5):401-7 PMID: 11532900
  27. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.
    J Clin Invest. 2007 Jan;117(1):195-205 PMID: 17200719
  28. The chemokine binding protein M3 prevents diabetes induced by multiple low doses of streptozotocin.
    J Immunol. 2007 Apr 1;178(7):4623-31 PMID: 17372021
  29. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.
    J Clin Invest. 2007 Apr;117(4):902-9 PMID: 17364026
Article Info
Journal
Circulation
Abbr.
Circulation
ISSN
1524-4539
DOI
10.1161/CIRCULATIONAHA.107.743872
Published
2008-04-01
Epub
2007-00-28
Pages
1642-8
Language
English
Region
United States
NLM ID
0147763
PMCID
PMC3589525
Subset
IM
Grants
NHLBI NIH HHS · 5R01 HL52773 · United States
NHLBI NIH HHS · R01 HL052773-16 · United States
NHLBI NIH HHS · R01 HL63894 · United States
NHLBI NIH HHS · R01 HL063894 · United States
NHLBI NIH HHS · R01 HL063894-08 · United States
NHLBI NIH HHS · R01 HL052773 · United States
NCRR NIH HHS · C06 RR018928 · United States
External Links
PubMed source DOI: 10.1161/CIRCULATIONAHA.107.743872 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2