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PMID: 16565511 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression.

The American journal of pathology ·Vol. 168 ·No. 4 ·2006-04-00 ·Pages 1385-95

Boisvert WA, Rose DM, Johnson KA, Fuentes ME, Lira SA, Curtiss LK, Terkeltaub RA

Abstract

Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR(-/-) mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-alpha; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR(-/-) background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2(-/-) mice despite robust MCP-1 expression. These studies indicate that KC/GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-alpha and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.

MeSH Terms
Animals Aorta/metabolism,pathology Atherosclerosis/metabolism,pathology Chemokine CCL2/metabolism Chemokine CXCL1 Chemokines, CXC/biosynthesis,genetics Chimera Intercellular Signaling Peptides and Proteins/biosynthesis,genetics Leukocytes/metabolism,pathology Macrophages/metabolism,pathology Male Mice Mice, Knockout Receptors, Interleukin-8B/biosynthesis,genetics Up-Regulation
Chemicals
Ccl2 protein, mouse Chemokine CCL2 Chemokine CXCL1 Chemokines, CXC Cxcl1 protein, mouse Intercellular Signaling Peptides and Proteins Receptors, Interleukin-8B
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Boisvert William A
Department of Immunology,* The Scripps Research Institute, La Jolla, California, USA. wboisvert@rics.bwh.harvard.edu
Rose David M
Johnson Kristen A
Fuentes Maria E
Lira Sergio A
Curtiss Linda K
Terkeltaub Robert A
References (43)
43 references, click to expand
  1. Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells.
    J Biol Chem. 1997 Nov 7;272(45):28568-73 PMID: 9353321
  2. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2.
    Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12053-8 PMID: 9342361
  3. Selective inhibition of expression of the chemokine receptor CCR2 in human monocytes by IFN-gamma.
    J Immunol. 1998 Apr 15;160(8):3869-73 PMID: 9558092
  4. 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
  5. 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
  6. Fibronectin: structure, assembly, and cardiovascular implications.
    Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1363-70 PMID: 9743223
  7. Chemokines and atherosclerosis.
    Curr Opin Lipidol. 1998 Oct;9(5):397-405 PMID: 9812193
  8. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL.
    Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1983-91 PMID: 9848893
  9. Interaction of very late antigen-4 with VCAM-1 supports transendothelial chemotaxis of monocytes by facilitating lateral migration.
    J Immunol. 1998 Dec 15;161(12):6825-34 PMID: 9862714
  10. Atherosclerosis--an inflammatory disease.
    N Engl J Med. 1999 Jan 14;340(2):115-26 PMID: 9887164
  11. Interaction between alpha 5 beta 1 integrin and secreted fibronectin is involved in macrophage differentiation of human HL-60 myeloid leukemia cells.
    J Immunol. 1999 Jan 1;162(1):407-14 PMID: 9886414
  12. Recent advances in chemokines and chemokine receptors.
    Crit Rev Immunol. 1999;19(1):1-47 PMID: 9987599
  13. 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
  14. Regulation of IL-8RA (CXCR1) expression in polymorphonuclear leukocytes by hypoxia/reoxygenation.
    J Leukoc Biol. 1999 Feb;65(2):171-8 PMID: 10088599
  15. Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice.
    Atherosclerosis. 1999 Mar;143(1):205-11 PMID: 10208497
  16. 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
  17. Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte function.
    J Lipid Res. 1999 Jun;40(6):1053-63 PMID: 10357837
  18. Peripheral blood mononuclear cell production of interleukin-8 and IL-8-dependent neutrophil function in hypercholesterolemic patients.
    Atherosclerosis. 1999 Oct;146(2):345-50 PMID: 10532690
  19. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes.
    J Immunol. 2000 Apr 1;164(7):3862-9 PMID: 10725748
  20. Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma.
    J Clin Invest. 2000 Sep;106(6):793-802 PMID: 10995790
  21. Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation.
    J Invest Dermatol. 2001 Feb;116(2):319-29 PMID: 11180010
  22. OxLDL upregulates growth-regulation oncogene alpha expression in human endothelial cells.
    Chin Med J (Engl). 2001 Dec;114(12):1240-4 PMID: 11793843
  23. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.
    Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5252-6 PMID: 2052604
  24. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.
    J Clin Invest. 1991 Dec;88(6):2039-46 PMID: 1752961
  25. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium.
    Arterioscler Thromb. 1993 Feb;13(2):197-204 PMID: 7678986
  26. Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity.
    Arterioscler Thromb. 1994 Jan;14(1):47-53 PMID: 8274477
  27. Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium.
    J Clin Invest. 1994 Nov;94(5):1968-73 PMID: 7962543
  28. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein.
    Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3893-7 PMID: 7732003
  29. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.
    Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8264-8 PMID: 7667279
  30. Production of chemokines, interleukin-8 and monocyte chemoattractant protein-1, during monocyte: endothelial cell interactions.
    Blood. 1995 Oct 1;86(7):2767-73 PMID: 7545470
  31. Distributions of melanoma growth stimulatory activity of growth-regulated gene and the interleukin-8 receptor B in human wound repair.
    Am J Pathol. 1995 Nov;147(5):1248-60 PMID: 7485389
  32. Thrombin induces GRO alpha/MGSA production in human umbilical vein endothelial cells.
    Thromb Res. 1995 Aug 15;79(4):387-94 PMID: 7482442
  33. Interleukin-8 production by macrophages from atheromatous plaques.
    Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):1007-12 PMID: 8696939
  34. Endothelial adhesion molecules in atherogenesis. A concerto or a solo?
    Circ Res. 1996 Dec;79(6):1216-7 PMID: 8943960
  35. Inflammatory and immunological nature of atherosclerosis.
    Int J Cardiol. 1996 Aug;54 Suppl:S51-60 PMID: 9119527
  36. Chemokines: leucocyte recruitment and activation cytokines.
    Lancet. 1997 Feb 15;349(9050):490-5 PMID: 9040590
  37. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection.
    Nature. 1997 Mar 20;386(6622):292-6 PMID: 9069289
  38. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4642-6 PMID: 9114044
  39. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.
    Am J Pathol. 1997 May;150(5):1687-99 PMID: 9137093
  40. Human chemokines: an update.
    Annu Rev Immunol. 1997;15:675-705 PMID: 9143704
  41. Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis.
    Arterioscler Thromb Vasc Biol. 1997 Jul;17(7):1289-302 PMID: 9261259
  42. The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.
    J Clin Invest. 1997 Sep 15;100(6):1575-80 PMID: 9294126
  43. 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
Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.2353/ajpath.2006.040748
Email
wboisvert@rics.bwh.harvard.edu
Published
2006-04-00
Pages
1385-95
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1606562
Subset
IM
Grants
NHLBI NIH HHS · R01 HL077360 · United States
NHLBI NIH HHS · HL-61731 · United States
NHLBI NIH HHS · R01 HL035297 · United States
NHLBI NIH HHS · HL-57934 · United States
NHLBI NIH HHS · HL-77360 · United States
NHLBI NIH HHS · HL-35297 · United States
External Links
PubMed source DOI: 10.2353/ajpath.2006.040748 PMC Full Text View journal details
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