Differential Role for Activating FcγRIII in Neointima Formation After Arterial Injury and Diet-Induced Chronic Atherosclerosis in Apolipoprotein E-Deficient Mice

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

Fcγ receptor activation mediates vascular inflammation and abdominal aortic aneurysm development

“…Autoantibodies specific for self‐derived epitopes participate in vascular inflammation and remodeling through mechanisms including phagocytosis and cell activation via FcγR following IC and complement deposition 38 . Studies in knockout mice lacking single or multiple FcγR isoforms have improved understanding of IgG‐FcγR interactions in autoimmune and cardiovascular diseases, particularly atherosclerosis 20,22,23 . In the context of AAA, gene sequencing identified upregulated “B cell receptor signaling” and “Fc receptor‐mediated phagocytosis” pathways in mouse AAA, 39,40 while microarray analysis 25 and immunohistochemistry 26 showed FcγRIIB expression in human AAA.…”

“…38 Studies in knockout mice lacking single or multiple FcγR isoforms have improved understanding of IgG-FcγR interactions in autoimmune and cardiovascular diseases, particularly atherosclerosis. 20,22,23 In the context of AAA, gene sequencing identified upregulated "B cell receptor signaling" and "Fc receptor-mediated phagocytosis" pathways in mouse AAA, 39,40 while microarray analysis 25 and immunohistochemistry 26 showed FcγRIIB expression in human AAA. Our study reveals expression of activating, γ-chain-associated FcγR (human IA and IIIA; mouse I, III, and IV) and inhibitory ITIM-bearing FcγRIIB (human/mouse) in the media and adventitia of AAA lesions.…”

“…17,18 By analyzing the phenotype of mice deficient in either individual FcγR or the common γ-chain, we and others have shown that activating FcγR contribute to atherosclerotic lesion formation, [20][21][22] while FcγRIIB has a controversial (both protective and pathogenic) role. 23,24 In the AAA setting, few studies so far have investigated FcγRIIB expression 25,26 and Syk activation 27 in human AAA; however, the function and cell types expressing FcγR have not been scrutinized. Therefore, the aim of this study is to explore the contribution of FcγR-mediated responses to inflammation and tissue injury during AAA formation.…”

Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development

“…The data generated in this model suggested that FcγR promoted atherosclerosis by inducing atheropathogenic Th17 responses [ 67 ]. The effect may be even more complex because a dichotomic role of FcγRIII in atherosclerosis depending on the lesion stage [ 68 ]. Differentiation of the effects mediated by direct recognition of oxLDL and interaction with oxLDL-IgG complexes can be challenging.…”

CCL2/CCR2 inhibition in atherosclerosis: a meta-analysis of preclinical studies

“…Models of accelerated atherosclerosis following arterial injury in atherosclerosis-prone mice were also considered eligible. [27][28][29] Studies referring to other animals beyond mice were not included in this review.…”