Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques.
Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques.
复制标题
干扰素调节因子-5依赖性CD11c+巨噬细胞有助于易破裂动脉粥样硬化斑块的形成。
DOI：
10.1093/eurheartj/ehab920
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发表时间：
2022-05-14
影响因子：
39.3
通讯作者：
Monaco, Claudia
中科院分区：
文献类型：
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作者：
Edsfeldt, Andreas;Swart, Maarten;Singh, Pratibha;Dib, Lea;Sun, Jiangming;Cole, Jennifer E;Park, Inhye;Al-Sharify, Dania;Persson, Ana;Nitulescu, Mihaela;Das Neves Borges, Patricia;Kassiteridi, Christina;Goddard, Michael E;Lee, Regent;Volkov, Petr;Orho-Melander, Marju;Maegdefessel, Lars;Nilsson, Jan;Udalova, Irina;Goncalves, Isabel;Monaco, Claudia
炎症是动脉粥样硬化的关键因素。转录因子干扰素调节因子-5 （IRF5）驱动巨噬细胞进入促炎状态。我们研究了IRF5在人类动脉粥样硬化和斑块稳定性中的作用。来自颈动脉斑块成像项目生物库的大量RNA测序用于挖掘主要巨噬细胞相关基因和转录因子与人类症状性颈动脉疾病之间的关联。使用免疫组织化学、接近延伸试验和飞行时间Helios细胞术（CyTOF）进行验证。在斑块破裂的诱导模型中，研究了IRF5缺乏对ApoE−/−小鼠颈动脉斑块表型和破裂的影响。干扰素调节因子-5和ITGAX/CD11c被鉴定为与症状性颈动脉疾病相关性最强的巨噬细胞相关基因。IRF5和ITGAX/CD11c的表达与易损性指数、促炎斑块细胞因子水平、坏死核心区相关，且相互之间存在相关性。细胞免疫组化和免疫组化结果显示，斑块中以巨噬细胞为主表达cd11c的免疫细胞。干扰素调节因子-5免疫阳性区域主要在CD11c+区域发现，并倾向于肩部区域，人类斑块最容易破裂的区域。因此，ApoE - / - Irf5 - / -诱导斑块破裂模型小鼠的颈动脉斑块破裂频率明显低于Irf5小鼠，坏死核心更小，CD11c+巨噬细胞更少。利用来自人颈动脉内膜切除术数据和IRF5缺陷小鼠颈动脉斑块诱导破裂的小鼠模型的补充证据，我们证明了促炎转录因子IRF5、巨噬细胞表型、斑块炎症及其破裂易感性之间的机制联系。巨噬细胞的促动脉粥样硬化和抗动脉粥样硬化功能取决于它们的转录状态和激活。通过人颈动脉内膜切除术和小鼠颈动脉斑块诱导破裂模型，我们发现转录因子干扰素调节因子-5 （IRF5）通过产生趋化因子CCL2和CCL4以及整合素CD11c的表达来促进巨噬细胞的激活，同时它使斑块内凋亡细胞（efferocytosis）摄取所需的蛋白质（如MFEG8和整合素ITGB3）的产生丧失能力。在此过程中，IRF5促进炎症，增加坏死核心的大小，增强斑块破裂的易感性。乳脂球-表皮生长因子-因子VIII；CCL2， C-C基序趋化因子配体2；CCL4， C-C基序趋化因子配体4；ITGB3，整合素亚基β 3。
Inflammation is a key factor in atherosclerosis. The transcription factor interferon regulatory factor-5 (IRF5) drives macrophages towards a pro-inflammatory state. We investigated the role of IRF5 in human atherosclerosis and plaque stability. Bulk RNA sequencing from the Carotid Plaque Imaging Project biobank were used to mine associations between major macrophage associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were used for validation. The effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE−/− mice was studied in an inducible model of plaque rupture. Interferon regulatory factor-5 and ITGAX/CD11c were identified as the macrophage associated genes with the strongest associations with symptomatic carotid disease. Expression of IRF5 and ITGAX/CD11c correlated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and with each other. Macrophages were the predominant CD11c-expressing immune cells in the plaque by CyTOF and immunohistochemistry. Interferon regulatory factor-5 immunopositive areas were predominantly found within CD11c+ areas with a predilection for the shoulder region, the area of the human plaque most prone to rupture. Accordingly, an inducible plaque rupture model of ApoE−/−Irf5−/− mice had significantly lower frequencies of carotid plaque ruptures, smaller necrotic cores, and less CD11c+ macrophages than their IRF5-competent counterparts. Using complementary evidence from data from human carotid endarterectomies and a murine model of inducible rupture of carotid artery plaque in IRF5-deficient mice, we demonstrate a mechanistic link between the pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and its vulnerability to rupture. Macrophages perform both pro- and anti-atherogenic functions depending on their transcriptional status and activation. Using human carotid endarterectomies and a murine model of inducible rupture of carotid plaque, we show that the transcription factor interferon regulatory factor-5 (IRF5) promotes macrophage activation with the production of chemokines CCL2 and CCL4, and the expression of the integrin CD11c ,while it disables the production of proteins required for the uptake of apoptotic cells within the plaque (efferocytosis) such as MFEG8 and the integrin ITGB3. In doing so, IRF5 promotes inflammation and increases the necrotic core size enhancing plaque vulnerability to rupture. MFGE8, Milk fat globule—epidermal growth factor—factor VIII; CCL2, C–C motif chemokine ligand 2; CCL4, C–C motif chemokine ligand 4; ITGB3, Integrin subunit beta 3.