Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice

作者：Zenghui Zhang, Maoxiong Wu, Lei Yao, Weibin Zhou, Xiao Liu, Zhiteng Chen, Ping Hua, Lei‐Bo Xu, Lei Lv, Chi-Yu Liu, Chunling Huang, Sixu Chen, Zhaoqi Huang, Yuna Huang, Jiaqi He, Tingfeng Chen, Jingfeng Wang, Woliang Yuan, Zhaoyu Liu, Yangxin Chen · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2024 · DOI：10.1161/atvbaha.124.321429 · 被引用次数：17 · 研究领域：Aortic Disease and Treatment Approaches、Inflammation biomarkers and pathways、Williams Syndrome Research

BACKGROUND: The development of aortic dissection (AD) is closely associated with inflammation. The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) signaling pathway critically regulates innate immunity and has emerged as an important target in cardiovascular diseases; however, its role in AD remains unclear. METHODS: Transcriptome data from human and mouse ADs were used to perform differentially expressed gene–based protein-protein interaction network analyses. Tyrobp knockout (Tyrobp −/− ), myeloid cell–specific Tyrobp −/− (Tyrobp fl/fl Lyz2 cre ), and Trem2 knockout (Trem2 −/− ) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in Tyrobp deficiency–mediated AD progression, macrophages were depleted using clodronate liposomes. Bulk and single-cell RNA sequencing, immunofluorescence staining, and quantitative real-time polymerase chain reaction were performed to assess inflammation and the underlying mechanisms of Tyrobp in AD. RESULTS: Network analysis identified Tyrobp as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell–specific deficiency of Tyrobp in mice significantly increased AD incidence and exacerbated extracellular matrix degradation and macrophage infiltration within the aortic wall. Macrophage depletion mitigated the adverse effects of Tyrobp deficiency on AD progression. Addi...