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

Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1858-63. doi: 10.1161/01.ATV.0000231527.22762.71. Epub 2006 Jun 8.

Abstract

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)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Bone Marrow / metabolism*
  • Bone Marrow Transplantation*
  • Chimera
  • Collagen / metabolism
  • Diet, Atherogenic
  • Female
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR5 / deficiency
  • Receptors, CCR5 / metabolism*
  • Receptors, LDL / deficiency*
  • Whole-Body Irradiation

Substances

  • Receptors, CCR5
  • Receptors, LDL
  • Collagen