Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions.

Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE^-/-) mice and ApoE^-/- mice with a genetic deletion of IRF5 (ApoE^-/-Irf5^-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.

Results: Both lesion and necrotic core size were significantly reduced in ApoE^-/-Irf5^-/- mice compared with IRF5-competent ApoE^-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c⁺ macrophages was evident in ApoE^-/-Irf5^-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c⁺ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c^- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.

Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c⁺ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.

中文翻译：

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干扰素调节因子5通过损害红细胞增多作用来控制动脉粥样硬化病变中的坏死核心形成

背景：髓样细胞是动脉粥样硬化病变发展和易损斑块形成的关键。动脉吞噬细胞摄取凋亡细胞的能力受损（胞吞作用）会促进病变的生长和坏死核心的建立。转录因子干扰素调节因子（IRF）-5是髓样功能和程序的重要调节剂。我们试图调查是否IRF5影响动脉粥样硬化病变的形成和表型。

方法：我们在两个互补模型中研究了IRF5在动脉粥样硬化中的作用。首先，比较高脂血症载脂蛋白E缺乏（ApoE ^-/-）小鼠和具有IRF5基因缺失（ApoE ^-/- Irf5 ^-/-）的ApoE ^-/-小鼠的动脉粥样硬化病变发展，然后在剪切应力调制的易损斑块形成模型。

结果：与具有IRF5能力的ApoE ^-/-小鼠相比，ApoE ^-/- Irf5 ^--/-小鼠的病变和坏死核心大小均显着减少。在剪切应力调制的易损斑块形成模型中，坏死核的大小也减小了。在主动脉，引流淋巴结和骨髓细胞培养物中的ApoE ^-/- Irf5 ^-/-小鼠中，CD11c ⁺巨噬细胞明显减少，这表明IRF5在动脉粥样硬化中维持CD11c ⁺巨噬细胞。此外，我们揭示了CD11c基因是巨噬细胞中IRF5的直接靶标。在没有IRF5的，CD11c的^- 巨噬细胞显示出调节胞吞整合素β3及其配体乳脂球-表皮生长因子8蛋白的表达显着增加，并在体外和原位增强了胞吞作用。

结论： IRF5通过促进病变内促炎性CD11c ⁺巨噬细胞的维持并通过削弱胞吞作用来控制坏死核心的扩张而对动脉粥样硬化有害。