Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231527.22762.71
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Role of Bone Marrow–Derived CC-Chemokine Receptor 5 in the Development of Atherosclerosis of Low-Density Lipoprotein Receptor Knockout Mice
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.
Correspondence to Ziad Mallat, Inserm U689, Hôpital Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France. E-mail mallat{at}larib.inserm.fr
Objective— CC chemokine receptor CCR5 is expressed by atheroma-associated cells and could mediate leukocyte attraction into developing lesions. We examined the role of bone marrow-derived CCR5 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.
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 in low-density lipoprotein-receptor–deficient mice. We showed that 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 were not sustained in the very advanced stages of atherosclerosis.
Key Words: atherosclerosis • chemokines • cytokines • inflammation
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