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Differential Role for Activating Fc?RIII 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 (Fc?Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc?RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc?RIII in diet-induced "chronic" atherosclerosis. Fc?rIII-/-/Apoe-/- and control Apoe-/- mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). Fc?rIII 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-? (TNF-?), 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 Fc?RIII in an early versus advanced stage of the disease. While Fc?rIII deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, Fc?rIII 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 Fc?rIII 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, Fc?RII, and Fc?RIV. Moreover, Fc?rIII-deficient macrophages expressed more Fc?rII, Tnf-?, and Il-1? 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 Fc?RIII 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 Fc?RIII in atherogenic inflammation.

SUBMITTER: Asare Y

PROVIDER: S-EPMC7313534 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Asare Yaw Y Koehncke Janine J Selle Jaco J Simsekyilmaz Sakine S Jankowski Joachim J Shagdarsuren Gansuvd G Gessner Johannes E JE Bernhagen Jürgen J Shagdarsuren Erdenechimeg E

Frontiers in physiology 20200617

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 i ...[more]

PMID: 32625118

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Project description:Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE-/- mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis.

Dataset Information

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

Publications

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

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