Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages
Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages
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清道夫受体 A1 通过促进巨噬细胞的胞吞作用减轻主动脉夹层
DOI：
10.1016/j.bcp.2019.07.027
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发表时间：
2019
影响因子：
5.8
通讯作者：
Chen Qi
中科院分区：
文献类型：
--
作者：
Zhang Zhi;Jiang Yunlong;Zhou Zhongqiu;Huang Jianan;Chen Shichao;Zhou Wenying;Yang Qing;Bai Hui;Zhang Hanwen;Ben Jingjing;Zhu Xudong;Li Xiaoyu;Chen Qi
巨噬细胞A1类清道夫受体（SR-A1）是一种在心血管疾病中具有抗炎功能的模式识别受体。然而，其在急性主动脉夹层（AD）中的作用尚不清楚。利用SR-A1缺陷小鼠及其野生型幼崽的主动脉夹层模型，我们发现SR-A1缺陷加重了-氨基丙腈引起的胸主动脉扩张、假腔形成、细胞外基质降解、血管炎症和凋亡细胞积累。这些病理变化与体内酪氨酸-蛋白激酶受体酪氨酸3介导的巨噬细胞efferocytosis受损有关。SR-A1可以直接与Tyro3相互作用，并且是Tyro3磷酸化激活其下游PI3K/Akt信号通路所必需的。重要的是，SR-A1−/−巨噬细胞与凋亡的Jurkat细胞共培养，导致吞噬的凋亡细胞减少，线粒体肿胀，ATP生成受损，IL-10分泌不足，TNF-α分泌旺盛。SR-A1的缺乏不影响吞噬酶体的形成。慢病毒在SR-A1−/−巨噬细胞中过表达Tyro3诱导体外恢复性吞噬作用。给予Tyro3激动剂蛋白S可恢复SR-A1−/−巨噬细胞体外和体内的吞噬能力。这些发现表明巨噬细胞中的SR-A1-Tyro3轴通过促进efferocysis和抑制炎症来减轻AD损伤。
Macrophage class A1 scavenger receptor (SR-A1) is a pattern recognition receptor with an anti-inflammatory feature in cardiovascular diseases. However, its role in acute aortic dissection (AD) is not known yet. Using an aortic dissection model in SR-A1-deficient mice and their wild type littermates, we found that SR-A1 deficiency aggravated beta-aminopropionitrile monofumarate induced thoracic aortic dilation, false lumen formation, extracellular matrix degradation, vascular inflammation and accumulation of apoptotic cells. These pathological changes were associated with an impaired macrophage efferocytosis mediated by tyrosine-protein kinase receptor Tyro3in vitroandin vivo. SR-A1 could directly interact with Tyro3 and was required for Tyro3 phosphorylation to activate its downstream PI3K/Akt signaling pathway. Importantly, co-culture of SR-A1−/−macrophages with apoptotic Jurkat cells resulted in less devoured apoptotic cells accompanied by swelling mitochondria and damaged ATP generation, following poor IL-10 and robust TNF-α production. Deficiency of SR-A1 did not influence phagolysosome formation during the efferocytosis. Lentiviral overexpression of Tyro3 in SR-A1−/−macrophages induced restorative phagocytosisin vitro. Administration of Tyro3 agonist protein S could restore SR-A1−/−macrophages phagocytosisin vitroandin vivo. These findings suggest that SR-A1-Tyro3 axis in macrophages mitigate AD damage by promoting efferocytosis and inhibiting inflammation.