ACKR1hiECs Promote Aortic Dissection Through Adjusting Macrophage Behavior.

Abstract

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.