BACKGROUND Type A aortic dissection (TAAD) is a life-threatening condition characterized by complex pathophysiology, in which macrophages play a critical but not yet fully understood role. This study focused on the role of endothelial cells with elevated expression of ACKR1 (atypical chemokine receptor 1) and their interaction with proinflammatory macrophages in TAAD development. METHODS AND RESULTS Single-cell transcriptomic analysis of human aortic tissues revealed increased populations of endothelial cells exhibiting high ACKR1 expression and proinflammatory macrophages in TAAD samples. Both clinical and animal studies revealed that ACKR1 expression levels were strongly linked to TAAD severity. Gain- and loss-of-function studies demonstrated that ACKR1 promotes TAAD progression. Specific knockdown of ACKR1 in endothelial cells suppressed the NF-κB (nuclear factor-κB) signaling pathway and SPP1 (secreted phosphoprotein 1) expression, leading to reduced macrophage migration and proinflammatory polarization, which subsequently inhibited TAAD development. Conversely, ACKR1 overexpression accelerated TAAD progression. Notably, molecular docking and comprehensive evaluation identified amikacin as a potential novel modulator of ACKR1. Extensive in vitro and in vivo studies demonstrated that amikacin can regulate macrophage behavior through the ACKR1/NF-κB/SPP1 signaling pathway, thereby attenuating TAAD progression and improving survival rates in TAAD mice. CONCLUSIONS This study reveals how endothelial cells exhibiting high ACKR1 expression modulate macrophage migration and proinflammatory polarization through the ACKR1/NF-κB/SPP1 signaling pathway, a crucial mechanism in TAAD progression. Targeting ACKR1 through both functional and pharmacological approaches effectively suppressed TAAD progression and extended survival in TAAD mice, offering promising new intervention strategies for clinical evaluation.

中文翻译：

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ACKR1hiECs 通过调整巨噬细胞行为促进主动脉夹层。


背景 A 型主动脉夹层 （TAAD） 是一种危及生命的疾病，其特征是复杂的病理生理学，其中巨噬细胞起着关键但尚未完全了解的作用。本研究侧重于 ACKR1 （非典型趋化因子受体 1） 表达升高的内皮细胞的作用及其与促炎巨噬细胞在 TAAD 发育中的作用。方法和结果 人主动脉组织的单细胞转录组学分析显示，TAAD 样本中表现出高 ACKR1 表达的内皮细胞群和促炎巨噬细胞群增加。临床和动物研究均显示，ACKR1 表达水平与 TAAD 严重程度密切相关。功能获得性和丧失研究表明，ACKR1 促进 TAAD 进展。内皮细胞中 ACKR1 的特异性敲低抑制了 NF-κB （核因子-κB） 信号通路和 SPP1 （分泌型磷蛋白 1） 表达，导致巨噬细胞迁移和促炎极化减少，从而抑制了 TAAD 的发展。相反，ACKR1 过表达加速了 TAAD 进展。值得注意的是，分子对接和综合评估确定阿米卡星是 ACKR1 的潜在新型调节剂。广泛的体外和体内研究表明，阿米卡星可以通过 ACKR1/NF-κB/SPP1 信号通路调节巨噬细胞行为，从而减弱 TAAD 进展并提高 TAAD 小鼠的存活率。结论 本研究揭示了表现出高 ACKR1 表达的内皮细胞如何通过 ACKR1/NF-κB/SPP1 信号通路调节巨噬细胞迁移和促炎极化，这是 TAAD 进展的关键机制。 通过功能和药理学方法靶向 ACKR1 可有效抑制 TAAD 进展并延长 TAAD 小鼠的生存期，为临床评估提供有前景的新干预策略。