Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10.
The chemokine RANTES has been implicated in neointimal hyperplasia after arterial injury. We analyzed the differential role of the RANTES receptors CCR1 and CCR5 by genetic deletion in apolipoprotein E-deficient mice. Deficiency in CCR5 significantly reduced neointimal area after arterial wire injury, associated with a decrease in macrophages, CD3(+) T lymphocytes, and CCR2(+) cells. In contrast, CCR1 deficiency did not affect neointimal area or cell content. Deletion of CCR5 entailed an up-regulation of the anti-inflammatory cytokine interleukin 10 (IL-10) in neointimal smooth muscle cells, and its antibody blockade reversed effects in CCR5(-/-) mice. Conversely, proinflammatory interferon gamma was increased in the neointima of CCR1(-/-) mice, and its blockade unmasked a reduction in macrophage recruitment. Our data indicate that CCR5 is more crucial than CCR1 for neointimal plaque formation, and that its attenuation in CCR5(-/-) mice is due to an atheroprotective immune response involving IL-10. This harbors important implications for targeting chemokine receptors in vascular remodeling.
Zernecke
Alma
A
Department of Cardiology, Rheinisch-Westfälische Technische Hochschule Aachen University, Germany.
Liehn
Elisa A
EA
Gao
Ji-Liang
JL
Kuziel
William A
WA
Murphy
Philip M
PM
Weber
Christian
C
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D017252:CD3 Complex; D002452:Cell Count; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000502:physiology; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology; D017539:Tunica Intima / Q000473:pathology*
D017252:CD3 Complex; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D016753:Interleukin-10; D007371:Interferon-gamma