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

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 gamma Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc gamma RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc gamma RIII in diet-induced chronic atherosclerosis.Fc gamma rIII(-/-)/Apoe(-/-)and controlApoe(-/-)mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD).Fc gamma rIIIdeficiency 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-alpha (TNF-alpha), 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 gamma RIII in an early versus advanced stage of the disease. WhileFc gamma rIIIdeficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end,Fc gamma rIIIdeficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect ofFc gamma rIIIdeficiency 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 gamma RII, and Fc gamma RIV. Moreover,Fc gamma rIII-deficient macrophages expressed moreFc gamma rII,Tnf-alpha, andIl-1 beta mRNA when exposed to IgG1 or oxLDL-IgG1 ICsin vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activatingFc gamma RIIIlimits 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 gamma RIII in atherogenic inflammation

Kompressionskräfte am hinteren Beckenring bei instabilen B/C-Frakturen: Neues modulares Kompressionsmodul zur verbesserten Applikation des supraazetabulären Beckenfixateurs

Atherogenic processes and vascular remodelling after arterial injury are controlled and driven by a plethora of factors amongst which the activation of the complement system is pivotal. Recently, we reported a clear correlation between high expressions of the second receptor for complement anaphylatoxin C5a, the C5a receptor-like 2 (C5L2, C5aR2), with high pro-inflammatory cytokine expression in advanced human atherosclerotic plaques. This prompted us to speculate that C5aR2 might have a functional role in atherosclerosis. We, therefore, investigated the role of C5aR2 in atherosclerosis and vascular remodelling. Here, we demonstrate that C5ar2 deletion, in atherosclerosis-prone mice, attenuates atherosclerotic as well as neointimal plaque formation, reduces macrophages and CD3+ T cells and induces features of plaque stability, as analysed by histomorphometry and quantitative immunohistochemistry. As a possible underlying mechanism, C5ar2-deficient plaques showed significantly reduced expression of C5a receptor (C5ar1), Tnf-? as well as Vcam-1, as determined by qPCR and quantitative immunohistochemistry. In addition, in vitro mechanistic studies revealed a reduction of these pro-inflammatory and pro-atherosclerotic mediators in C5ar2-deficient macrophages. Finally, blocking C5ar1 with antagonist JPE1375, in C5ar2(-/-)/Apoe(-/-) mice, led to a further reduction in neointimal plaque formation with reduced inflammation. In conclusion, C5ar2 deficiency attenuates atherosclerosis and neointimal plaque formation after arterial injury. This identifies C5aR2 as a promising target to reduce atherosclerosis and restenosis after vascular interventions