Role of bone marrow-derived CC-chemokine receptor 5 in the development of atherosclerosis of low-density lipoprotein receptor knockout mice.
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.


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)-alpha 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.


CONCLUSIONS
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-alpha. These effects are not sustained in the very advanced stages of atherosclerosis.
Potteaux
Stéphane
S
Institut National de la Santé et de la Recherche Médicale, INSERM U689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France.
Combadière
Christophe
C
Esposito
Bruno
B
Lecureuil
Cedric
C
Ait-Oufella
Hafid
H
Merval
Régine
R
Ardouin
Patrice
P
Tedgui
Alain
A
Mallat
Ziad
Z
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002678:Chimera; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D005260:Female; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency*; D014916:Whole-Body Irradiation
D019713:Receptors, CCR5; D011973:Receptors, LDL; D003094:Collagen