Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice.
BACKGROUND
Monocytes/macrophages play a central role in many stages of development of atherosclerotic plaques, including the conversion to an unstable morphology with rupture and fissuring. A better understanding of the mechanism of attachment of monocytes to activated endothelial cells would prove useful in developing strategies aimed at blocking this initial step. Here we describe a novel in vivo model that directly demonstrates homing of macrophages to atherosclerotic plaques.


RESULTS
Macrophages were loaded with fluorescent microspheres and injected intravenously into 40-week-old apolipoprotein E-deficient mice. After 48 hours, labeled macrophages were observed adhering to all stages of atherosclerotic plaques from the early fatty streak to mature calcified lesion. The mean number of macrophages adherent to atherosclerotic plaques located in the proximal 1 mm of the aortic root was quantitated by counting serial frozen sections and found to be 143 +/- 17 macrophages per aortic root. Pretreatment of the apolipoprotein E-deficient mice with monoclonal antibodies directed against the alpha-subunit of the alpha4beta1 integrin and against intracellular cell adhesion molecule (ICAM-1) reduced macrophage homing by 75% and 65%, respectively, as compared with isotype-matched controls (P<.05). Pretreatment with a monoclonal antibody directed against E-selectin did not significantly reduce macrophage homing.


CONCLUSIONS
These data demonstrate that alpha4 integrin and ICAM-1 play major roles in the recruitment of macrophages to atherosclerotic plaques, whereas E-selectin does not appear to contribute significantly to macrophage recruitment. This model will be useful for studying the mechanism of macrophage recruitment to atherosclerotic plaques and for evaluating the efficacy of inhibitors to adhesion molecules in preventing macrophage recruitment.
Patel
S S
SS
Department of Internal Medicine, University of Texas Health Sciences Center, Houston 77030, USA.
Thiagarajan
R
R
Willerson
J T
JT
Yeh
E T
ET
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology*; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000276:immunology / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D005260:Female; D039441:Integrin alpha4; D016023:Integrins / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4