Fcγ Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice

Abstract

Abstract-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 Ϫ/Ϫ ) with Fc␥R ␥ chain-deficient mice (␥ Ϫ/Ϫ ). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE Ϫ/Ϫ control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49Ϯ6% and 56Ϯ8%, respectively, compared with the content in apoE Ϫ/Ϫ 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 ␥ Ϫ/Ϫ and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-B activation. ApoE Ϫ/Ϫ mice have higher levels of activating Fc␥RI and Fc␥RIIIA, and inhibitory Fc␥RIIB, compared with wild-type mice. The DKO mice express only the inhibitory Fc␥RIIB receptor. We conclude that Fc␥R deficiency limits development and progression of atherosclerosis. In addition to leukocytes, Fc␥R 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 Fc␥Rs in atherogenesis and support the use of immunotherapy in the treatment of this disease. Key Words: Fc receptors Ⅲ atherosclerosis Ⅲ double-knockout mice Ⅲ immune complexes A therosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells, and extracellular matrix. In recent years, the immune processes associated to atherogenesis have received considerable attention. Studies in both humans and animals have demonstrated that atheromatous lesions at all stage of development contain a wide variety of cells and molecules characteristic of immune system, such as macrophages, lymphocytes, CD40, interferon-␥, major histocompatibility complex-II, complement, and antibodies (Abs). [1][2][3][4] In addition, congenital deficiency of macrophages, T and B lymphocytes, or even the inhibition of their mediators has resulted in the reduction of atherosclerotic lesion. 1,3 One of the critical steps in atherogenesis is the accumulation within the arterial intima of cholesteryl ester-laden foam cells, many of them derived from macrophages, whose formation is ultimately dependent on the uptake of various forms of low-density lipoproteins (LDLs). 1,2 Although emphasis has been placed on scavenger receptors, foam-cell development may also be influenced by lipoprotein interaction with other receptors, such as LDL receptors, very-low-density lipoprotein (VLDL) receptors, and IgG Fc (Fc␥Rs) receptors. 5 Diff...

Atherogenesis and the humoral immune response to modified lipoproteins

“…Signaling through FcγR is also responsible for the activation of MonoMac cells which results in the release of pro-inflammatory cytokines [12]. A recent report that double KO mice, Apo-E −/− and FcγR −/− , seem protected against the development of atherosclerosis [62] can be considered as indirect evidence of the involvement of LDL-IC in this animal model, because modified lipoproteins or free antibodies to those modified lipoproteins will not interact with Fcγ receptors.…”

Requirement for Vav Proteins in Post-Recruitment Neutrophil Cytotoxicity in IgG but Not Complement C3-Dependent Injury

“…Recent data suggest that tissue injury associated with IgG and/or complement deposition in tissue may be attributed to the activity of these receptors. A deficiency in activating Fc␥Rs protects from immune complex (IC) 4 -mediated inflammation in the kidney (2,3), joints (4), skin (5,6), lung (7,8), and heart (9). A deficiency in Mac-1 is associated with a reduction in complement C3-mediated inflammation in the kidney (10) and skin (11,12).…”

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

“…[15][16][17] Activating FcgRs (I, III, and IV) are associated with the immunoreceptor tyrosine-based activation motif-harboring common g-chain, and upon ligand binding they stimulate phagocytosis, oxidative burst, and cytokine release, whereas inhibitory FcgRIIb nullifies cell activation. 13,14 Altered FcgR expression has been found in patients and experimental models, [18][19][20][21] and clinical studies have shown an association between different FcgR genotypes with diabetes and cardiovascular risk. 22,23 In this study we examined the relevance of FcgRs to the pathogenesis of diabetic nephropathy in a model of type 1 diabetes accelerated by hypercholesterolemia.…”