Fcgamma receptor deficiency confers protection against atherosclerosis in apolipoprotein E knockout mice.
IgG Fc receptors (FcgammaRs) 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 FcgammaR gamma chain-deficient mice (gamma(-/-)). 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-kappaB (NF-kappaB) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both gamma(-/-) and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-kappaB activation. ApoE(-/-) mice have higher levels of activating FcgammaRI and FcgammaRIIIA, and inhibitory FcgammaRIIB, compared with wild-type mice. The DKO mice express only the inhibitory FcgammaRIIB receptor. We conclude that FcgammaR deficiency limits development and progression of atherosclerosis. In addition to leukocytes, FcgammaR 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 FcgammaRs in atherogenesis and support the use of immunotherapy in the treatment of this disease.
Hernández-Vargas
Purificación
P
Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
Ortiz-Muñoz
Guadalupe
G
López-Franco
Oscar
O
Suzuki
Yusuke
Y
Gallego-Delgado
Julio
J
Sanjuán
Guillermo
G
Lázaro
Alberto
A
López-Parra
Virginia
V
Ortega
Luis
L
Egido
Jesús
J
Gómez-Guerrero
Carmen
C
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017452:Receptors, IgG / Q000172:deficiency* / Q000378:metabolism
D000936:Antigen-Antibody Complex; D001057:Apolipoproteins E; D018925:Chemokines; C517507:FcgammaRIIIA protein, mouse; C485701:Fcgr1 protein, mouse; C499172:Fcgr2b protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D017452:Receptors, IgG