Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
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DOI：
10.1172/jci80300
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Ravichandran, Kodi S.
中科院分区：
文献类型：
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作者：
Fond, Aaron M.;Lee, Chang Sup;Ravichandran, Kodi S.
巨噬细胞每天清除数百万个凋亡细胞，并在此过程中摄取大量胆固醇。膜转运蛋白ABCA 1是巨噬细胞胆固醇流出的关键参与者，并已通过人类遗传研究显示可提供对心血管疾病的保护。凋亡细胞清除过程如何与巨噬细胞A8CA 1表达相关尚不清楚。在这里，我们确定了一个质膜启动的信号通路，驱动ABCA 1 mRNA和蛋白质的快速上调。该途径涉及吞噬受体脑特异性血管生成因子1（BAI1），其识别凋亡细胞上的磷脂酰丝氨酸，以及细胞内信号中间体吞噬细胞运动1（ELMO 1）和Rac 1，因为ABCA 1诱导在缺乏这些分子的小鼠的原代巨噬细胞中减弱。此外，这种凋亡细胞启动的途径独立于已知调节ABCA 1表达和胆固醇流出的肝脏X受体（LXR）甾醇传感机制发挥作用。当被置于高脂肪饮食中时，缺乏BAI 1的小鼠在其主动脉根部的凋亡细胞数量增加，这与脂质谱的改变有关。与此相反，与对照动物相比，转基因BAI 1过表达的工程小鼠的巨噬细胞显示出更大的ABCA 1诱导凋亡细胞。总的来说，这些数据确定了一个膜启动的途径，该途径由凋亡细胞触发，以增强吞噬吞噬细胞内的ABCA 1，并在体内产生功能性后果。
Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage A8CA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.