Published online before print October 19, 2006, doi: 10.1161/01.RES.0000250556.07796.6c
© 2006 American Heart Association, Inc.
Molecular Medicine |
Fc
Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice
From the Renal and Vascular Research Laboratory (P.H.-V., G.O.-M., O.L.-F., J.G.-D., G.S., A.L., V.L.-P., J.E., C.G.-G.), Fundación Jiménez Díaz, Autónoma University, Madrid, Spain; Division of Nephrology (Y.S.), Department of Internal Medicine, Juntendo University, Tokyo, Japan; and Pathology Department (L.O.), Hospital Clínico, Complutense University, Madrid, Spain.
Correspondence to Carmen Gómez-Guerrero, PhD, Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Autónoma University, Avda. Reyes Católicos, 2, Madrid 28040, Spain. E-mail cgomez{at}fjd.es
IgG Fc receptors (Fc
Rs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E–deficient mice (apoE–/–) with FcR chain–deficient mice (–/–). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE–/– control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49±6% and 56±8%, respectively, compared with the content in apoE–/– lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-
B (NF-B) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both –/– and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-B activation. ApoE–/– mice have higher levels of activating FcRI and FcRIIIA, and inhibitory FcRIIB, compared with wild-type mice. The DKO mice express only the inhibitory FcRIIB receptor. We conclude that FcR deficiency limits development and progression of atherosclerosis. In addition to leukocytes, FcR activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of FcRs in atherogenesis and support the use of immunotherapy in the treatment of this disease.
Key Words: Fc receptors • atherosclerosis • double-knockout mice • immune complexes
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