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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.  Fc γ rIII –/– /Apoe –/–   and control  Apoe –/–   mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD).  Fc γ 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-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  Fc γ rIII  deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end,  Fc γ 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 γ 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, FcγRII, and FcγRIV. Moreover,  Fc γ rIII -deficient macrophages expressed more  Fc γ rII ,  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  Fc γ 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 FcγRIII in atherogenic inflammation.

frontiers in physiology

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