on June 8, 2006
Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231527.22762.71
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Submitted on December 13, 2005
Accepted on May 18, 2006
Role of Bone Marrow-Derived CC-Chemokine Receptor 5 in the Development of Atherosclerosis of Low-Density Lipoprotein Receptor Knockout Mice
Stéphane Potteaux ;
From Institut National de la Santé et de la Recherche Médicale (S.P., B.E., H.A.O., R.M., A.T., Z.M.), INSERM U689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France; INSERM U543(C.C., C.L.), laboratoire d’Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France; and Institut Gustave Roussy (P.A., deceased), Villejuif, France.
* To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.
Objective--CC chemokine receptor CCR5 is expressed by atheroma-associated cells and could mediates leukocyte attraction into developing lesions. We examined the role of bone marrow-derived CCR5 the in the development of atherosclerotic lesions after 8, 12, or 35 weeks of high-fat diet.
Methods and Results--Low-density lipoprotein-receptor (LDLr)-deficient mice were lethally irradiated and transplanted with CCR5+/+ or CCR5-/- bone marrow. After 8 weeks of fat diet, CCR5 deficiency in leukocytes led to 30% decrease of macrophage accumulation within the fatty streak (P<0.05), with no change in lesion size. After 12 weeks of fat diet, CCR5 deficiency also resulted in 30% decrease of plaque-macrophage accumulation (P<0.005), associated with 16% reduction in lesion size in the aortic sinus (P=0.13), despite a significant increase in total cholesterol levels (P=0.03). Lesions with CCR5 deficiency showed 52% reduction in matrix metalloproteinase (MMP)-9 expression (P=0.02) and 2-fold increase in collagen accumulation (P<0.0001). These changes were associated with a significant increase of interleukin (IL)-10 mRNA expression in spleens of CCR5-/- mice compared with CCR5+/+ controls. In addition, we found enhanced IL-10 production by CCR5-deficient peritoneal macrophages and decreased tumor necrosis factor (TNF)-
production by CCR5-/- T cells in comparison with CCR5+/+ controls. CCR5-/- and CCR5+/+ reconstituted animals showed no differences in plaque size or composition after 35 weeks of high-fat diet despite the persistent absence of CCR5 in plaques of mice reconstituted with CCR5-/- bone marrow.
Conclusion--Bone marrow-derived CCR5 favors the development of an inflammatory and collagen-poor plaque phenotype in association with decreased macrophage-derived IL-10 and enhanced T cell-derived TNF-. These effects are not sustained in the very advanced stages of atherosclerosis.
Key words: atherosclerosis • chemokines • cytokines • inflammation
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