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PMID: 12569158 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis.

The Journal of clinical investigation ·Vol. 111 ·No. 3 ·2003-02-00 ·Pages 333-40

Lesnik P, Haskell CA, Charo IF

Abstract

The hallmark of early atherosclerosis is the accumulation of lipid-laden macrophages in the subendothelial space. Circulating monocytes are the precursors of these "foam cells," and recent evidence suggests that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Fractalkine (FK) is a structurally unusual chemokine that can act either as a soluble chemotactic factor or as a transmembrane-anchored adhesion receptor for circulating leukocytes. A polymorphism in the FK receptor, CX(3)CR1, has been linked to a decrease in the incidence of coronary artery disease. To determine whether FK is critically involved in atherogenesis, we deleted the gene for CX(3)CR1 and crossed these mice into the apoE(-/-) background. Here we report that FK is robustly expressed in lesional smooth muscle cells, but not macrophages, in apoE(-/-) mice on a high-fat diet. CX(3)CR1(-/-) mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation. Taken together, these data provide strong evidence that FK plays a key role in atherogenesis.

MeSH Terms
Animal Feed Animals Aorta/pathology Arteriosclerosis/genetics CD11b Antigen/biosynthesis CX3C Chemokine Receptor 1 Cell Movement Chemokine CX3CL1 Chemokines, CX3C/physiology Coronary Artery Disease/metabolism Dietary Fats Foam Cells/metabolism Genotype Membrane Proteins/physiology Mice Monocytes/metabolism Polymorphism, Genetic RNA, Messenger/metabolism Receptors, Chemokine/genetics,physiology Reverse Transcriptase Polymerase Chain Reaction Time Factors
Chemicals
CD11b Antigen CX3C Chemokine Receptor 1 CX3CL1 protein, human CX3CR1 protein, human Chemokine CX3CL1 Chemokines, CX3C Cx3cl1 protein, mouse Cx3cr1 protein, mouse Dietary Fats Membrane Proteins RNA, Messenger Receptors, Chemokine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lesnik Philippe
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141, USA.
Haskell Christopher A
Charo Israel F
References (33)
33 references, click to expand
  1. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.
    J Exp Med. 1998 Oct 19;188(8):1413-9 PMID: 9782118
  2. 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
  3. Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice.
    Atherosclerosis. 1999 Mar;143(1):205-11 PMID: 10208497
  4. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions.
    Nature. 1999 Apr 22;398(6729):718-23 PMID: 10227295
  5. 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
  6. Inflammatory agents regulate in vivo expression of fractalkine in endothelial cells of the rat heart.
    J Leukoc Biol. 1999 Dec;66(6):937-44 PMID: 10614775
  7. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion.
    Mol Cell Biol. 2000 Jun;20(11):4106-14 PMID: 10805752
  8. Unique role of the chemokine domain of fractalkine in cell capture. Kinetics of receptor dissociation correlate with cell adhesion.
    J Biol Chem. 2000 Nov 3;275(44):34183-9 PMID: 10940307
  9. Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100.
    J Clin Invest. 2000 Dec;106(12):1501-10 PMID: 11120757
  10. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse.
    Atherosclerosis. 2001 Feb 1;154(2):399-406 PMID: 11166772
  11. The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo.
    Am J Pathol. 2001 Mar;158(3):855-66 PMID: 11238035
  12. 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
  13. Generation and analysis of mice lacking the chemokine fractalkine.
    Mol Cell Biol. 2001 May;21(9):3159-65 PMID: 11287620
  14. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions.
    Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):923-9 PMID: 11397698
  15. 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
  16. Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection.
    J Clin Invest. 2001 Sep;108(5):679-88 PMID: 11544273
  17. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium.
    J Clin Invest. 2001 Nov;108(9):1307-14 PMID: 11696575
  18. Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine.
    J Biol Chem. 2001 Nov 30;276(48):44622-6 PMID: 11571300
  19. Fractalkine is expressed by smooth muscle cells in response to IFN-gamma and TNF-alpha and is modulated by metalloproteinase activity.
    J Immunol. 2002 Jan 15;168(2):604-12 PMID: 11777952
  20. Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS.
    Glia. 2002 Mar 15;37(4):314-27 PMID: 11870871
  21. Hypomorphic apolipoprotein E mice: a new model of conditional gene repair to examine apolipoprotein E-mediated metabolism.
    J Biol Chem. 2002 Mar 29;277(13):11064-8 PMID: 11792702
  22. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions.
    Am J Pathol. 1981 May;103(2):181-90 PMID: 7234961
  23. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.
    Arteriosclerosis. 1984 Jul-Aug;4(4):323-40 PMID: 6466191
  24. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.
    Cell. 1992 Oct 16;71(2):343-53 PMID: 1423598
  25. Cell biology of atherosclerosis.
    Annu Rev Physiol. 1995;57:791-804 PMID: 7778883
  26. Down regulation of CD11b and CD18 expression in atherosclerotic lesion-derived macrophages.
    Am Surg. 1995 Aug;61(8):674-9; discussion 679-80 PMID: 7618805
  27. A new class of membrane-bound chemokine with a CX3C motif.
    Nature. 1997 Feb 13;385(6617):640-4 PMID: 9024663
  28. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation.
    Nature. 1997 Jun 5;387(6633):611-7 PMID: 9177350
  29. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion.
    Cell. 1997 Nov 14;91(4):521-30 PMID: 9390561
  30. Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation.
    J Clin Invest. 1997 Nov 1;100(9):2276-85 PMID: 9410905
  31. 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
  32. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia.
    Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10896-901 PMID: 9724801
  33. 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
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI15555
Published
2003-02-00
Pages
333-40
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151849
Subset
IM
Grants
NHLBI NIH HHS · R01 HL052773 · United States
NHLBI NIH HHS · R01 HL063894 · United States
NHLBI NIH HHS · HL-52773 · United States
NHLBI NIH HHS · HL-63894 · United States
Corrections
CommentIn
PMID: 12697729
External Links
PubMed source DOI: 10.1172/JCI15555 PMC Full Text View journal details
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