AUTHOR=Asare Yaw , Koehncke Janine , Selle Jaco , Simsekyilmaz Sakine , Jankowski Joachim , Shagdarsuren Gansuvd , Gessner Johannes E. , Bernhagen Jürgen , Shagdarsuren Erdenechimeg 

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

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00673

DOI=10.3389/fphys.2020.00673

ISSN=1664-042X

ABSTRACT=<p>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. <italic>Fc</italic>γ<italic>rIII<sup>–/–</sup>/Apoe<sup>–/–</sup></italic> and control <italic>Apoe<sup>–/–</sup></italic> mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). <italic>Fc</italic>γ<italic>rIII</italic> 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 <italic>Fc</italic>γ<italic>rIII</italic> deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, <italic>Fc</italic>γ<italic>rIII</italic> 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 <italic>Fc</italic>γ<italic>rIII</italic> 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, <italic>Fc</italic>γ<italic>rIII</italic>-deficient macrophages expressed more <italic>Fc</italic>γ<italic>rII</italic>, <italic>Tnf-α</italic>, and <italic>Il-1β</italic> mRNA when exposed to IgG1 or oxLDL-IgG1 ICs <italic>in vitro</italic>, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activating <italic>Fc</italic>γ<italic>RIII</italic> 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.</p>