Sphingosine-1-phosphate, a novel TREM2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury.
Sphingosine-1-phosphate, a novel TREM2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury.
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1-磷酸鞘氨醇是一种新型 TREM2 配体，可促进小胶质细胞吞噬作用以预防缺血性脑损伤
DOI：
10.1016/j.apsb.2021.10.012
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发表时间：
2022-04
影响因子：
14.5
通讯作者：
Sun, Xiulan
中科院分区：
文献类型：
--
作者：
Xue, Tengfei;Ji, Juan;Sun, Yuqin;Huang, Xinxin;Cai, Zhenyu;Yang, Jin;Guo, Wei;Guo, Ruobing;Cheng, Hong;Sun, Xiulan
1-磷酸鞘氨醇 (S1P) 介导的吞噬作用的机制仍不清楚。在这里，我们发现 S1P 或 FTY720（S1P 的类似物）独立于 S1PR 促进中风中的小胶质细胞吞噬作用。首先，我们使用分子对接的计算机模拟来预测S1P可能是触发骨髓细胞2（TREM2）表达的受体的配体。接下来，通过微尺度热泳动（MST）、表面等离振子共振（SPR）和液相色谱-串联质谱（LC-MS/MS）揭示S1P是一种新型TREM2配体。然后，我们证实了 Trem2-Dap12 转染的 CHO 细胞和 TREM2 敲低小胶质细胞中 S1P 靶向的促吞噬作用。点突变分析表明D104是关键的结合残基。 Trem2−/− 小鼠被用来证明 S1P 诱导的针对 TREM2 的吞噬作用在预防缺血性脑损伤中的作用。最后，进一步研究发现，负载S1P的载脂蛋白E（APOE）由小胶质细胞释放，并通过LDL受体相关蛋白1B（LRP1B）与凋亡神经元结合，从而诱导小胶质细胞吞噬凋亡神经元。总的来说，本研究首次揭示了S1P作为TREM2的新型内源性配体，可以有效促进小胶质细胞的吞噬作用。我们的研究结果为开发针对 TREM2 的免疫调节剂提供了一种新的先导化合物。 S1P 与 TREM2 相互作用，增加小胶质细胞的吞噬作用，并在缺血性中风中发挥神经保护作用。凋亡神经元显示膜 LRP1B 表达增加，介导 S1P-TREM2 诱导的清除。
The mechanism of sphingosine-1-phosphate (S1P)-mediated phagocytosis remains unknown. Here, we found that S1P or FTY720 (an analog of S1P) promoted microglial phagocytosis in stroke independent of S1PRs. First, we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). Next, microscale thermophoresis (MST), surface plasmon resonance (SPR) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) were performed to reveal that S1P was a novel TREM2 ligand. Then, we confirmed the pro-phagocytosis of S1P targeting in Trem2-Dap12 transfected CHO cells and TREM2 knockdown microglia. Point mutation analysis showed that D104 was the critical binding residue. Trem2−/− mice were used to demonstrate the role of S1P-induced phagocytosis targeting on TREM2 in protecting against ischemic brain injury. Finally, further studies revealed that apolipoprotein E (APOE) loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B (LRP1B) and thereby induced microglia to phagocytose apoptotic neurons. Overall, the present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis. Our findings provide a new lead compound for developing immunomodulator targeting on TREM2. S1P interacts with TREM2 to increase microglial phagocytosis and exerts neuroprotective effect in ischemic stroke. Apoptotic neurons showed increased membrane LRP1B expression to mediate S1P-TREM2 induced clearance.
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影响因子：
5.6
作者：
Mecca C;Giambanco I;Donato R;Arcuri C
通讯作者：
Arcuri C
核内SphK2-S1P轴通过抑制HDAC1介导的KLF4脱乙酰化促进小胶质细胞M1到M2的转变
影响因子：
7.3
作者：
Ji, Juan;Wang, Juan;Sun, Xiu-Lan
通讯作者：
Sun, Xiu-Lan
芬戈莫德改变脑出血中的炎症介质和血管通透性
影响因子：
5.6
作者：
Li, Yu-Jing;Chang, Guo-Qiang;Yan, Yaping
通讯作者：
Yan, Yaping
影响因子：
4.4
作者：
Daws, MR;Sullam, PM;Seaman, WE
通讯作者：
Seaman, WE
DOI：
10.1083/jcb.200808080
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
N'Diaye EN;Branda CS;Branda SS;Nevarez L;Colonna M;Lowell C;Hamerman JA;Seaman WE
通讯作者：
Seaman WE