The role of Fc γ receptors in atherosclerosis

Abstract

Atherosclerosis is widely considered to be an immune-mediated process. Fcγ receptors (Fcγ Rs) contribute to the regulation of a multitude of immune and inflammatory responses and are implicated in human atherosclerotic lesions. Major cell types involved in the pathogenesis of atherosclerosis express Fcγ Rs and their proatherogenic ligands such as immune complexes and C-reactive protein, which act to activate Fcγ R signaling pathways. This review summarizes recent significant progress addressing the multifaceted roles of Fcγ Rs in atherogenesis which comes from the studies of Fcγ R-deficient animal models, clinical investigations and in vitro molecular and cellular studies. These new findings help us appreciate the emerging role of Fcγ Rs in atherosclerosis, and suggest Fcγ Rs as a potential therapeutic target for atherosclerosis.

Keywords

atherosclerosis immune complexes C-reactive protein

Introduction

It is well established that atherosclerosis is a chronic inﬂammatory disease of the wall of large- and medium-sized arteries where both innate and adaptive immunity responses play a pivotal role in the initiation, growth and rupture of atherosclerotic plaques.¹ The receptors for the Fc region of IgG (Fc γ Rs) are members of the Ig superfamily and are widely expressed in the hematopoietic system where they regulate the immune and inflammatory responses.² Increasing lines of evidence suggest that Fc γ Rs are implicated in the pathogenesis of atherosclerosis. Systemic autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and antiphospholipid syndrome, are characterized by accelerated atherosclerosis partly due to the presence of autoantibodies and autoantigens, and the subsequent formation of immune complexes (ICs).^3,4 Moreover, several autoantibodies such as those directed against oxidized low-density lipoprotein (oxLDL) and heat shock proteins have been detected in atherosclerotic lesions.^5–8 ICs may form between these antigens and autoantibodies that promote the progression of atherosclerosis via Fc γ R cross-linkage and activation as well as complement activation.⁹ In addition, C-reactive protein (CRP), a crucial mediator of cardiovascular disease, elicits a wide array of proatherogenic effects in a majority of cell types involved in atherogenesis, mostly mediated via Fc γ R-dependent pathways.¹⁰ In this review, we summarize recent studies addressing the multifaceted roles of Fc γ Rs in atherosclerosis.

The family of Fc γ Rs

Most Fc γ Rs are activating receptors and consist of the high-affinity receptor Fc γ RI and a family of low-affinity receptors, including Fc γ RIIA, Fc γ RIIC, Fc γ RIIIA and Fc γ RIIIB in humans, and Fc γ RIII and Fc γ RIV in mice.¹¹ Activated Fc γ Rs result in the phosphorylation of immunoreceptor tyrosine-based activating motifs, leading to the activation of the signaling molecule SYK and the initiation of the downstream signaling cascade. Fc γ RIIB is conserved in mice and humans and is the only known inhibitory Fc γ R which transmits inhibitory signals through an immunoreceptor tyrosine-based inhibitory motif contained in its cytoplasmic region.² Cross-linking of activated Fc γ Rs results in pathogen clearance by antibody-dependent cellular cytotoxicity, degranulation and phagocytosis, as well as the release of cytokines and other inﬂammatory mediators. Fc γ RIIB is co-expressed with activated Fc γ Rs on inﬂammatory effector cells such as neutrophils and macrophages and negatively regulates activating signals delivered by these receptors.^12,13 Thus, the family of Fc γ Rs provides a prime example of how simultaneous triggering of activating and inhibitory signaling pathways sets the threshold for cell activation to maintain a well-balanced immune response.¹⁴

Although human and mouse have orthologous Fc γ Rs and, in both species, most of the corresponding genes are clustered in close proximity to each other in syntenic regions on chromosome 1,¹² the human Fc γ R system is more complex, and the comparison of Fc γ Rs between human and mouse is shown in Table 1.^2,11,12

Table 1

Comparison of Fc γ Rs between human and mouse

	Mouse				Human
	Fc γ RI	Fc γ RIIB	Fc γ RIII	Fc γ RIV	Fc γ RIA	Fc γ RIIA	Fc γ RIIB	Fc γ RIIC	Fc γ RIIIA	Fc γ RIIIB
Signaling pathways	ITAM FcR- γ	ITIM	ITAM FcR- γ	ITAM FcR- γ	ITAM FcR- γ	ITAM	ITIM	ITAM	ITAM FcR- γ
Affinity	High	Low	Low	Low	High	Low	Low	Low	Low	Low
Monocytes/macrophages	+	+	+	+	+	+	+	−	+	−
Neutrophils	+	+	+	+	+	+	+	−	−	+
Dentritic cells	+	+	+	−	+	+	+	−	+	−
B-cells	−	+	−	−	−	−	+	−	−	−
Mast cells	−	−	−	−	−	−	+	−	−	+
Fc γ R variants	None				Fc γ RIIA-R/H131Fc γ RIIB-I/T232Fc γ RIIIA-F/V158 Fc γ RIIIB-Na1/Na2
IgG isotype	IgG1 IgG2a IgG2b IgG3				IgG1 IgG2 IgG3 IgG4

Fc γ R, Fc γ receptor; ITAM, immunoreceptor tyrosine-based activating motif; ITIM, immunoreceptor tyrosine-based inhibitory motif

Proatherogenic effects of Fc γ Rs

Fc γ Rs are expressed not only by immune cells such as dendritic cells, macrophages, monocytes, neutrophils, mast cells and B-cells,^2,15 but also by platelets, endothelial cells and vascular smooth muscle cells,^2,16,17 Although B-cells, dendritic cells, mast cells and neutrophils express significant amounts of Fc γ Rs and have been shown to play a role in atherosclerosis, there are few investigations into the contribution to atherosclerosis of Fc γ Rs expressed in these cells. This review focuses on the proatherogenic effects of monocytes/macrophages and vascular cells via Fc γ R-dependent pathways.

Macrophage-derived foam cells are important constituents of atheromatous lesions. In addition to the scavenger receptor pathway, the uptake of immune-complexed lipoproteins through Fc γ Rs represents another pathway of macrophage foam cell development. Treatment of monocytes with LDL-ICs containing intact anti-LDL antibody could dramatically increase the ability of these cells to subsequently bind and take up LDL, whereas aggregated LDL or ICs of LDL prepared with F(ab’)2 fragments of anti-LDL antibody had no significant effect.¹⁸ These results suggest that the formation and interaction of ICs of LDL with Fc γ Rs on monocytic cells is involved in the generation of macrophage-derived foam cells. Indeed, foam cell development of monocytes was enhanced by targeting LDL aggregates to Fc γ RI or Fc γ RII, and this was accompanied by an apparent impairment of LDL degradation through using bispecific antibodies consisting of anti-LDL monoclonal antibodies conjugated to anti-Fc γ R monoclonal antibodies.¹⁹ Further study confirmed that the uptake of LDL ICs by macrophages predominantly through Fc γ RI led to the transformation of macrophages into foam cells.²⁰ In addition, high-density lipoprotein (HDL) inhibits the uptake of modified LDL by macrophages, likely through interfering with CD36 and Fc γ RI expression.²¹ Notably, enhanced CD36 expression in monocytes has been proposed to link autoimmunity and atherosclerosis.²²

Human macrophages are efficiently activated by LDL-ICs mediated by Fc γ Rs, as reflected by the release of interleukin-1β (IL-1β) and tumor necrosis factor-α and the accumulation of oxygen active radicals.²³ A subsequent study showed that these effects were due to Fc γ RI-mediated activation of the mitogen-activated protein kinase signaling pathway, thus leading to macrophage activation.²⁴ Moreover, LDL-ICs localized in atherosclerotic lesions induced macrophage matrix metalloproteinase-1 (MMP-1) secretion by cross-linking Fc γ RI with Fc γ RII.²⁵ The survival and proliferation of macrophages play a critical role in the pathogenesis of vascular inflammation.^26–28 oxLDL–IgG ICs promote the survival of monocytes by cross-linking Fc γ RI with ensuing activation of Akt-dependent survival signaling.²⁹ On the other hand, Luo et al.³⁰ recently reported that Fc γ R activation through cross-linking stimulated macrophage proliferation via the activation of ERK1/2 signaling pathway and the subsequent transcriptional activation of cyclin D1 expression. These results imply that the activation of Fc γ R on macrophages may exert a mitogenic effect similar to growth factors and consequently stimulate macrophage proliferation. Taken together, it is clear that the Fc γ R-mediated immune reaction induces a variety of metabolic and functional changes in macrophages which are likely to contribute, directly or indirectly, to endothelial damage and the accumulation of macrophages in human atherosclerotic lesions.

Endothelial cells also express Fc γ Rs and are crucially involved in atherosclerosis.^16,31 Sumiyoshi et al.³² were the ﬁrst to show that the deletion of the FcR γ chain preserves the endothelial function and attenuates oxidative stress induced by hypercholesterolaemia in FcR γ ^−/− mice. Fc γ R also mediated monocyte adhesion to oxLDL-IC deposited on endothelium and the subsequent release of chemokines.³³ Thus, the interaction between Fc γ Rs and oxLDL-IC may be another mechanism responsible for vascular endothelial cell injury that could contribute to the progression of atherosclerosis. A recent study demonstrated that endothelial nitric oxide synthase (eNOS) antagonism by CRP or ICs is mediated by the coupling of Fc γ RI to Fc γ RIIB and the subsequent activation of Src kinase and SH2 domain-containing inositol 5′-phosphatase 1. Therefore, Fc γ RI and Fc γ RIIB emerge as novel therapeutic targets for preventing endothelial dysfunction in inflammatory or IC-mediated conditions.³⁴

Increased platelet expression of Fc γ RIIa may contribute to greater platelet reactivity and has been associated with a high risk of subsequent cardiovascular events.^35,36 Interferon- γ selectively upregulated the expression of Fc γ RIIa in cells exhibiting the characteristics of megakaryocytes.³⁷ Konishi et al.³⁸ demonstrated that Fc γ Rs played a pivotal role in the initiation and generation of neointimal hyperplasia after balloon injury in Fc γ R-deficient mice through the activation of platelets by collagen. They further confirmed that collagen-induced activation of platelets through Fc γ Rs aggravated the extension of myocardial ischemia–reperfusion injury.³⁹

Potential role of Fc γ Rs in atherosclerosis: insight from animal models

Fc γ Rs have been detected in human atherosclerotic lesions using immunocytochemical techniques,¹⁰ which suggests a potential role for Fc γ Rs in the formation of arterial lesions and provides further support to the hypothesis that Fc γ Rs engage ICs during atherogenesis. Indeed, Ig treatment reduced atherosclerosis in apoE knockout mice,^40,41 and the antiatherosclerotic effects of Ig have been attributed to Fc γ R-mediated anti-inﬂammatory and immunomodulatory actions.⁴¹

A number of in vivo studies in Fc γ R genetically altered mice have been reported (Table 2). Fc γ R deficiency conferred protection against the development of atherosclerosis in apoE^−/− γ ^−/− double knockout mice.^42,43 In particular, apoE^−/− γ ^−/− mice demonstrated a reduced size of atherosclerotic lesions along the aorta compared with their corresponding apoE ^−/− controls. Furthermore, the macrophage and T-cell contents, the expression of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, regulated on activated normal T-cell expressed and secreted and the activation of nuclear factor-κB in aortic lesions from apoE^−/− γ ^−/− mice were significantly reduced compared with apoE^−/−controls. Interestingly, Fc γ RI and Fc γ RIII of apoE^−/− γ ^−/− mice did not function, while Fc γ RIIB expression was upregulated in the aorta. Thus, in addition to the deﬁciency of activating Fc γ RI and Fc γ RIIIA, the upregulation of inhibitory Fc γ RIIB might provide an alternative explanation for the atheroprotection. Zhao et al.⁴⁴ further evaluated the role of the inhibitory Fc γ RIIB in atherosclerosis in a hypercholesterolemic low-density lipoprotein receptor (LDL-R)-deﬁcient mice model transplanted with Fc γ RIIB-deﬁcient bone marrow cells. They observed that the plaque area in the descending aorta was signiﬁcantly larger in mice transplanted with Fc γ RIIB-deﬁcient bone marrow cells than in mice transplanted with control normal bone marrow cells. However, no differences in plasma cholesterol or triglyceride concentrations between the two groups were found. Moreover, Fc γ RIIB deﬁciency resulted in ampliﬁed splenocyte proliferative response to Con A stimulation, enhanced expression of major histocompatibility complex class II on B-cells, and enlarged amount of CD25 + CD4 T-cells and B-cells in the spleen. Therefore, it appears that Fc γ RIIB deﬁciency promotes atherogenesis by inducing an imbalance of stimulatory and inhibitory immune cells. A very recent study reported that male apoE^−/−Fc γ RIIb^−/− mice developed exacerbated atherosclerosis that was independent of lipid levels, and was characterized by increased antibody titers to modiﬁed LDL and proinﬂammatory cytokines in the aorta.⁴⁵ Moreover, Kelly et al. ⁴⁶ found that arterial lesion formation was dramatically decreased at the advanced stage of atherogenesis in Fc γ RIII^−/−LDLR^−/− mice compared with LDLR^−/− controls, and this was associated with increased production of IL-10 by an expansion of CD4 + T-cells and upregulated IgG1 and IgG2c titers to oxLDL. Collectively, these new results suggest that antibodies against atherosclerosis-associated antigens partially protect against atherosclerosis by conveying inhibitory signals through Fc γ RIIb that downregulates proinﬂammatory signaling via other immune receptors.

Table 2

Atherosclerosis studies on genetic manipulation of Fc γ Rs in the mouse model

Mouse model	Plasma lipids	Lesion size	Cellular composition	Cytokines	Immune response	Ref.
apoE^−/− γ ^−/−	↔	↓	Lesion: macrophages↓	Lesion: MCP-1↓	IC-induced NF-κB activation↓	42
			T-cells↓	ICAM-1↓RANTES↓
LDLR^−/−+Fc γ RIIB^−/−BMT	↔	↑	Spleen:CD4⁺CD25⁺T-cells↑	Plasma: IL-10↑IL-4↑	Splenocyte proliferative response↑	44
			B-cells↑	IL-5↑	anti-oxLDL IgG2a/c↑
apoE^−/− Fc γ RIIb^−/−	↔	↑	Lesion: macrophages ↔	Lesion: IL-1β↑TNFα↑	B-cell responses to modiﬁed LDL↑	45
			T-cells↑	IL-17A↑IL-23↑
LDLR^−/−Fc γ RIII^−/−	TC↑	↓	Lesion: macrophages↓	Lesion, plasma, spleen: IL-10↑	anti-oxLDL IgG1, IgG2c↑	46
			T-cells↑	IFN- γ ↑

IFN- γ , interferon- γ ; TNFα, tumor necrosis factor-α; oxLDL, oxidized LDL; ICAM-1, intercellular adhesion molecule-1; RANTES, regulated on activated normal T-cell expressed and secreted; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; BMT, bone marrow transplantation; TC, total cholesterol; ↑, increase; ↓, decrease; ↔, none

Fc γ R polymorphisms and expression in the vascular atherosclerotic disease: insight from clinical studies

Accumulating evidence based on epidemiological studies has shown that Fc γ Rs are associated with a variety of atherosclerotic and thrombotic disorders (summarized in Table 3). The association between Fc γ R polymorphisms and coronary atherosclerosis (CAD) was first reported by Gavasso et al.,⁴⁷ who genotyped Fc γ RIIA-R/H131, Fc γ RIIIB-Na1/Na2 and Fc γ RIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography, and found that Fc γ RIIIA-F/V158 polymorphisms were linked to a strong protective effect because patients homozygous for the Fc γ RIIIA-V158 allele had a signiﬁcantly reduced risk of CAD. Later studies confirmed that Fc γ RIIA-R/H131 polymorphism is not an independent risk indicator of coronary artery disease, including patients with acute coronary syndrome (ACS).^48–52 However, a recent study demonstrated a genetic association of Fc γ RIIa R/R131 genotype with a more frequent occurrence of ACS.⁵³ In addition, the Fc γ RIIA-R/H131 genotype was shown to be associated with endothelial dysfunction, advanced peripheral atherosclerosis and carotid artery intima-media thickness.^54–56

Table 3

Association of Fc γ R polymorphisms with coronary artery disease

Fc γ R alleles	Study population	Number studied	Association	Ref.
Fc γ RIIA-R/H131	Caucasian	882 patients with CAG, 96 controls	No association with CAD; Fc γ RIIA and	47
Fc γ RIIIB-Na1/Na2			Fc γ RIIIB genotypes; Fc γ RIIIA-V/V158
Fc γ RIIIA-F/V158			protective against CAD
Fc γ RIIA-R/H131	Caucasian	MONICA: 527 patients with a history of MI, 527 controls	No association	48
		LURIC: 2227 patients with CAD, 1032 controls
Fc γ RIIA-R/H131	German	2391 patients with CAG, 510 controls	No association	49
Fc γ RIIA-R/H131	Caucasian	506 patients with acute MI, 468 controls	No association with risk of MI	50
Fc γ RIIA-R/H131	Australia	66 patients with SAP, 105 patients with UAP	No association	51
Fc γ RIIA-R/H131	German	701 patients with ACS, 467 patients with SAP, 684 controls	Fc γ RIIA-R/R131 associated with ACS	53

CAG, coronary angiography; SAP, stable angina pectoris; UAP, unstable angina pectoris; CAD, coronary artery disease; MI, myocardial infarction; ACS, acute coronary syndrome

Macrophages play a crucial role in the development of vascular lesions in atherogenesis. Soluble Fc γ RIIIa^MΦ derived from macrophages is present in the plasma. The level of sFc γ RIIIa^MΦ was associated with the severity of coronary atherosclerosis in CAD patients and positively correlated with LDL-cholesterol/HDL-cholesterol ratio, but was negatively correlated with HDL-cholesterol level.⁵⁷ Moreover, sFc γ RIIIa^MΦ concentration in the plasma was correlated with carotid maximum intima-media thickness and a number of risk factors for atherosclerosis, such as aging, current smoking, diabetes, hypertension, LDL-cholesterol/HDL-cholesterol ratio and family history of atherosclerotic diseases.⁵⁸ These ﬁndings indicate that the macrophages are activated during the process of atherosclerosis, and sFc γ RIIIa^MΦ serves as a novel biomarker for atherosclerosis. Pfeiffer et al.⁵⁹ performed quantitative ﬂow cytometry to measure the expression of Fc γ RI and Fc γ RIIA on peripheral monocytes in patients with severe atherosclerosis, and found that the expression of Fc γ RIIA on peripheral monocytes was signiﬁcantly decreased in patients with clinical atherosclerosis compared with control subjects and it was positively correlated with serum HDL-cholesterol concentrations. Based on these data, the expression of Fc γ RIIA may be proposed as a marker for assessing relative risk of atherosclerotic disease.

Collagen-mediated platelet activation contributes significantly to coronary and cerebrovascular thrombus formation associated with atherosclerotic plaque destabilization. Both collagen and Fc γ RIIA cross-linking have been shown to activate platelets via the tyrosine kinase Syk signaling pathway.⁶⁰ Calverley and co-workers^35,36 showed that the expression of Fc γ RIIA on platelet surface was increased in patients with acute coronary or cerebrovascular events, and patients with diabetes mellitus or uremia. Therefore, increased platelet Fc γ RIIA expression may also contribute to increased risk of atherothrombotic events.

The interaction of Fc γ Rs with CRP in atherosclerosis

Although the binding of CRP to Fc γ Rs is still under debate,^61–63 a research group has recently provided the quantitative characterization of CRP binding to Fc γ Rs by using ultrasensitive confocal imaging analysis.^64–66 Another study also presented structural and functional evidence for the involvement of pentraxins, including serum amyloid P component and CRP, in the activation of Fc γ Rs.⁶⁷ While there is an ongoing debate whether CRP participates actively in atherogenesis or is merely an innocent bystander, growing amounts of data have shown that CRP elicits a proinflammatory and proatherogenic role, ranging from fatty streak formation to clinical events, mostly mediated via Fc γ R-dependent pathways.^10,68

Several studies have indicated that CRP binds to Fc γ RI and Fc γ RII in monocytes.^69–71 CRP stimulates the expression of MMP-1,⁷² MMP-9,⁷³ receptor for advanced glycation end products and its inflammatory ligand AGE,⁷⁴ decreases IL-10 secretion,⁷⁵ and induces high-mobility group box-1 protein release⁷⁶ through Fc γ Rs in monocytes/macrophages. CRP also promotes macrophage colony-stimulating factor release⁷⁷ and CC chemokine receptor 2 expression via Fc γ Rs,⁷⁸ leading to the accumulation of monocytes in the atherogenic arterial wall. Moreover, CRP promotes oxidized LDL uptake via Fc γ Rs which contribute to foam cell formation in vitro and in vivo.^79,80

CRP binds and interacts with Fc γ RI and Fc γ RII in endothelial cells,⁸¹ which induces endothelial cell apoptosis,⁷³ promotes monocyte–endothelial cell adhesion,¹⁶ inhibits eNOS activity,⁸² and uncouples eNOS.⁸³ Fc γ Rs also mediates CRP-induced reactive oxygen species generation and tissue factor expression in vitro and in vivo.^17,84,85 Notably, a recent study found that exaggerated neointima formation in human CRP transgenic mice depended on the presence of Fc γ RI.⁸⁶

Perspectives

Immune responses participate in every phase of atherosclerosis and Fc γ Rs play a crucial role in regulating a multitude of innate and adaptive immune responses.^87,88 Accumulating body of evidences have suggested the role of Fc γ Rs in the development of atherosclerosis and a summary of the potential cellular effects of Fc γ Rs in atherosclerosis is presented in Figure 1. The new findings based on Fc γ R knockout mouse models have provided valuable information to decipher the role of Fc γ Rs in atherosclerosis in human. Nevertheless, due to the differences of Fc γ Rs in human and mouse, the future challenge is to develop novel humanized models to elucidate the pathophysiological role of the different classes of human Fc γ Rs in atherogenesis.

Figure 1

The potential cellular effects mediated by Fc γ receptors (Fc γ R) in atherosclerosis. The interaction of Fc γ receptors with immune complexes or C-reactive protein induces a series of proatherogenic pathological reactions. Fc γ R-mediated macrophage activation promotes survival and proliferation of macrophages, increases macrophage-derived foam cell formation and enhances release of proinflammatory mediators, e.g. IL-1β, TNFα, MMP1, MMP10, leading to the accumulation of macrophages in human atherosclerotic lesions and vulnerable plaque. On the other hand, Fc γ R-mediated immune reaction results in endothelial dysfunction, including eNOS uncoupling, eNOS activity inhibition, excessive oxidative stress, endothelial cell apoptosis and adhesion augmentation and induces tissue factor expression and activation of platelets, which are associated with an increased risk of cardiovascular events. Dendritic cells and B-cells are also implicated in the development of atherosclerosis. Potential antiatherosclerotic mechanisms mediated by Fc γ Rs in these cells remain to be elucidated. Moreover, Fc γ RIIB alleviates arterial lesion progression in animal models although the molecular mechanisms have not been fully understood. IL-1β, interleukin-1β; TNFα, tumor necrosis factor-α; MMP, matrix metalloproteinase; eNOS, endothelial nitric oxide synthase. (A color version of this figure is available in the online journal)

Undoubtedly, a deeper understanding of the role of Fc γ Rs in atherosclerosis will help design a new strategy for the prevention and treatment of atherosclerosis. Statins, widely used for treating atherosclerosis, inhibit Fc γ R signaling by disrupting membrane rafts to decrease the release of inﬂammatory mediators by monocyte/macrophage.⁸⁹ Therefore, targeting Fc γ Rs will open up new opportunities for atherosclerosis prevention and therapy, although the development and application of intravenous Ig, engineered Fc γ fragments and monoclonal anti-Fc γ R antibodies in vivo presents formidable technical challenges. Finally, optimizing antibody activity by enhancing the interaction with the inhibitory Fc γ Rs, or blocking antibody binding to the stimulatory Fc γ Rs, might represent novel immunotherapeutic approaches for atherosclerosis.

Author contributions: XW and XL searched the literature and wrote the manuscript; ZY provided supervision and revised the manuscript; and CK provided comments and suggestion on the manuscript.

Footnotes

ACKNOWLEDGEMENTS

This study was supported by the National Basic Research Program of China (‘973 Program’ No. 2012 CB517804 to ZY), National Science Fund of China for Distinguished Young Scholars (NSFC 81025002 to ZY) and NSFC (No. 30871043 to ZY).

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