Abstract
Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (FcγRs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of FcγRIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of FcγRIII in diet-induced “chronic” atherosclerosis. FcγrIII–/–/Apoe–/– and control Apoe–/– mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). FcγrIII deficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of FcγRIII in an early versus advanced stage of the disease. While FcγrIII deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, FcγrIII deficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect of FcγrIII deficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, FcγRII, and FcγRIV. Moreover, FcγrIII-deficient macrophages expressed more FcγrII, Tnf-α, and Il-1β mRNA when exposed to IgG1 or oxLDL-IgG1 ICs in vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activating FcγRIII limits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of FcγRIII in atherogenic inflammation.
Highlights
As a chronic and progressive inflammatory condition of the arterial vessel wall, atherosclerosis is initiated by the recruitment of inflammatory cells and the accumulation of oxidized low density lipoproteins that jointly drive the progression of atherosclerotic plaque development (Bernhagen et al, 2007; Weber and Noels, 2011; Libby et al, 2013)
Given that plaque immunoglobulin G (IgG)-type antibodies are generally considered to be atherogenic, while IgMs predominantly exhibit atheroprotective activity (Schmitz et al, 2018; Sage et al, 2019), these findings suggest the need of FcγRIII for clearance of pro-atherogenic immune complexes (ICs) against modified lipoproteins, and may at least partly explain the exacerbated atherosclerotic lesion formation observed upon FcγrIII deficiency
Our study investigated the role of activating FcγRIII in neointima expansion after arterial injury and in dietinduced chronic atherosclerosis in Apolipoprotein E-deficient hypercholesterolemic mice, comparing the phenotype in early versus intermediate-to-late stages
Summary
As a chronic and progressive inflammatory condition of the arterial vessel wall, atherosclerosis is initiated by the recruitment of inflammatory cells and the accumulation of oxidized low density lipoproteins (oxLDL) that jointly drive the progression of atherosclerotic plaque development (Bernhagen et al, 2007; Weber and Noels, 2011; Libby et al, 2013). FcγRs are important cell-surface receptors on hematopoietic cells and are able to bind to immunoglobulin G (IgG) This binding capacity induces a variety of biological responses like inflammatory cell activation, phagocytosis and antibody-dependent cellular cytotoxicity as well as maintenance of immunoglobulin homeostasis (Nimmerjahn and Ravetch, 2008). These receptors are classified as “activating” (FcγRI, III, and VI) and “inhibiting” (FcγRII) receptors In spite of their differences (activating versus inhibiting), FcγRs generally play a crucial role in the clearance of IC-containing oxidized LDL. Binding of oxLDL-IC to FcγR on macrophages can activate a variety of pro-inflammatory cell responses These include the release of inflammatory molecules such as Tnf-α and the complement component C5a, as well as the transformation of macrophages into foam cells, an important hallmark mechanism of atherosclerosis (Kiener et al, 1995)
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