Zhang Zenghui, Wu Maoxiong, Yao Lei, Zhou Weibin, Liu Xiao, Chen Zhiteng, Hua Ping, Xu Leibo, Lv Lei, Liu Chiyu, Huang Chunling, Chen Sixu, Huang Zhaoqi, Huang Yuna, He Jiaqi, Chen Tingfeng, Wang Jingfeng, Yuan Woliang, Liu Zhaoyu, Chen Yangxin
Department of Cardiology (Z.Z., M.W., W.Z., X.L., Z.C., C.L., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Y.C.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation (Z.Z., M.W., L.Y., W.Z., X.L., Z.C., C.L., C.H., S.C., Z.H., Y.H., J.H., T.C., J.W., W.Y., Z.L., Y.C.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Arterioscler Thromb Vasc Biol. 2025 Jan;45(1):119-135. doi: 10.1161/ATVBAHA.124.321429. Epub 2024 Nov 7.
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.
Transcriptome data from human and mouse ADs were used to perform differentially expressed gene-based protein-protein interaction network analyses. knockout (Tyrobp), myeloid cell-specific (Tyrobp Lyz2), and knockout (Trem2) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in 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.
Network analysis identified as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell-specific deficiency of 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 deficiency on AD progression. Additionally, deficiency enhanced TLR (Toll-like receptor)-4 signaling and macrophage activation, which were abrogated by TLR4 inhibitors. Furthermore, deletion of the Tyrobp-associated receptor significantly aggravated mouse AD development, whereas Trem2 agonist treatment conferred protection against AD.
Our findings suggest a novel role for the Trem2/Tyrobp axis in AD development in mice. Enhancement of Trem2/Tyrobp signaling may represent a promising strategy for the prevention and treatment of AD. Future studies to clarify the role of Trem2/Tyrobp in human AD are warranted.
主动脉夹层（AD）的发生与炎症密切相关。髓系细胞触发受体2（Trem2）/TYRO蛋白酪氨酸激酶结合蛋白（Tyrobp）信号通路对先天免疫起着关键调节作用，并已成为心血管疾病的重要靶点；然而，其在AD中的作用尚不清楚。
利用人和小鼠AD的转录组数据进行基于差异表达基因的蛋白质-蛋白质相互作用网络分析。给敲除（Tyrobp）、髓系细胞特异性敲除（Tyrobp Lyz2）和敲除（Trem2）小鼠饮用含单氟马来酸β-氨基丙腈的水以诱导AD。为了剖析巨噬细胞在Tyrobp缺陷介导的AD进展中的作用，使用氯膦酸脂质体清除巨噬细胞。进行批量和单细胞RNA测序、免疫荧光染色以及定量实时聚合酶链反应，以评估AD中的炎症和Tyrobp的潜在机制。
网络分析确定Tyrobp为AD的枢纽基因，在人和小鼠AD中均观察到其水平升高。小鼠中Tyrobp的全身敲除和髓系细胞特异性缺陷显著增加了AD的发生率，并加剧了主动脉壁内的细胞外基质降解和巨噬细胞浸润。巨噬细胞清除减轻了Tyrobp缺陷对AD进展的不利影响。此外，Tyrobp缺陷增强了Toll样受体（TLR）-4信号传导和巨噬细胞活化，而TLR4抑制剂可消除这些作用。此外，敲除与Tyrobp相关的受体Trem2显著加重了小鼠AD的发展，而Trem2激动剂治疗则对AD具有保护作用。
我们的研究结果表明Trem2/Tyrobp轴在小鼠AD发生中具有新作用。增强Trem2/Tyrobp信号传导可能是预防和治疗AD的一种有前景的策略。未来有必要开展研究以阐明Trem2/Tyrobp在人类AD中的作用。
