Published online before print August 1, 2005, doi: 10.1161/CIRCULATIONAHA.104.520718
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;112:870-878.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo
From the Division of Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland (N.R.V., S.S., G.P., B.R.K., F.M.); Ina Sue Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, Mass (B.L., C.G.); Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco (I.F.C.); and Gladstone Institute of Cardiovascular Disease, San Francisco, Calif (I.F.C.).
Correspondence to François Mach, MD, Cardiology Division, Department of Medicine, University Hospital Geneva, Foundation for Medical Research, 64 Avenue Roseraie, 1211 Geneva 4, Switzerland. E-mail francois.mach{at}medecine.unige.ch
Received January 14, 2004; de novo received November 11, 2004; revision received April 20, 2005; accepted April 26, 2005.
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.
Key Words: atherogenesis • chemokine • immunology • inflammation • leukocytes
Related Article:
Circulation 2005 112: 777.
This article has been cited by other articles:
 |
|
 |
|
  K. Ayada, K. Yokota, K. Hirai, K. Fujimoto, K. Kobayashi, H. Ogawa, K. Hatanaka, S. Hirohata, T. Yoshino, Y. Shoenfeld, et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis Lupus, November 1, 2009; 18(13): 1154 - 1168. [Abstract] [PDF]
|
|
|
|
 |
|
 F. K. Swirski, R. Weissleder, and M. J. Pittet Heterogeneous In Vivo Behavior of Monocyte Subsets in Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1424 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zernecke, E. Shagdarsuren, and C. Weber Chemokines in Atherosclerosis: An Update Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1897 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schober Chemokines in Vascular Dysfunction and Remodeling Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1950 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Saederup, L. Chan, S. A. Lira, and I. F. Charo Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2-/- Mice: Evidence for Independent Chemokine Functions in Atherogenesis Circulation, April 1, 2008; 117(13): 1642 - 1648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Combadiere, S. Potteaux, M. Rodero, T. Simon, A. Pezard, B. Esposito, R. Merval, A. Proudfoot, A. Tedgui, and Z. Mallat Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6Chi and Ly6Clo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice Circulation, April 1, 2008; 117(13): 1649 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Ohman, Y. Shen, C. I. Obimba, A. P. Wright, M. Warnock, D. A. Lawrence, and D. T. Eitzman Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 12, 2008; 117(6): 798 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J.A. van Wanrooij, S. C.A. de Jager, T. van Es, P. de Vos, H. L. Birch, D. A. Owen, R. J. Watson, E. A.L. Biessen, G. A. Chapman, T. J.C. van Berkel, et al. CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 251 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Walcher, K. Hess, P. Heinz, K. Petscher, D. Vasic, U. Kintscher, M. Clemenz, M. Hartge, K. Raps, V. Hombach, et al. Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-{gamma} Hypertension, February 1, 2008; 51(2): 259 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Barlic and P. M. Murphy Chemokine regulation of atherosclerosis J. Leukoc. Biol., August 1, 2007; 82(2): 226 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Mitchell and P. Libby Vascular Remodeling in Transplant Vasculopathy Circ. Res., April 13, 2007; 100(7): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ranjbaran, S. I. Sokol, A. Gallo, R. E. Eid, A. O. Iakimov, A. D'Alessio, J. R. Kapoor, S. Akhtar, C. J. Howes, M. Aslan, et al. An Inflammatory Pathway of IFN-{gamma} Production in Coronary Atherosclerosis J. Immunol., January 1, 2007; 178(1): 592 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Steffens, F. Burger, G. Pelli, Y. Dean, G. Elson, M. Kosco-Vilbois, L. Chatenoud, and F. Mach Short-Term Treatment With Anti-CD3 Antibody Reduces the Development and Progression of Atherosclerosis in Mice Circulation, October 31, 2006; 114(18): 1977 - 1984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ranjbaran, Y. Wang, T. D. Manes, A. O. Yakimov, S. Akhtar, M. S. Kluger, J. S. Pober, and G. Tellides Heparin Displaces Interferon-{gamma}-Inducible Chemokines (IP-10, I-TAC, and Mig) Sequestered in the Vasculature and Inhibits the Transendothelial Migration and Arterial Recruitment of T Cells Circulation, September 19, 2006; 114(12): 1293 - 1300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Heller, E. Liu, A. M. Tager, Q. Yuan, A. Y. Lin, N. Ahluwalia, K. Jones, S. L. Koehn, V. M. Lok, E. Aikawa, et al. Chemokine CXCL10 Promotes Atherogenesis by Modulating the Local Balance of Effector and Regulatory T Cells Circulation, May 16, 2006; 113(19): 2301 - 2312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Weber Killing Two Birds With One Stone: Targeting Chemokine Receptors in Atherosclerosis and HIV Infection Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2448 - 2450. [Full Text] [PDF]
|
|