The Intra-nuclear SphK2-S1P Axis Facilitates M1-to-M2 Shift of Microglia via Suppressing HDAC1-Mediated KLF4 Deacetylation
The Intra-nuclear SphK2-S1P Axis Facilitates M1-to-M2 Shift of Microglia via Suppressing HDAC1-Mediated KLF4 Deacetylation
复制标题
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
DOI：
10.3389/fimmu.2019.01241
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发表时间：
2019-06-04
影响因子：
7.3
通讯作者：
Sun, Xiu-Lan
中科院分区：
文献类型：
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作者：
Ji, Juan;Wang, Juan;Sun, Xiu-Lan
1-磷酸鞘氨醇 (S1P) 参与多种细胞反应，包括小胶质细胞激活和极化。然而，S1P 对缺血诱导的小胶质细胞激活和极化的影响仍不清楚。在本研究中，选择 Sprague-Dawley 大鼠进行大脑中动脉闭塞（MCAO）建立，并用 S1P 类似物 FTY720（0.5、1、2 mg/kg）治疗 24 小时。在原代培养的小胶质细胞中检查了 FTY720 对氧糖剥夺 (OGD) 诱导的小胶质细胞极化的影响。 FTY720治疗可以预防缺血引起的脑损伤和神经功能障碍，还可以降低大鼠IL-1β和TNF-α的水平并促进M2小胶质细胞极化。此外，我们发现 FTY720 抑制 OGD 损伤的小胶质细胞中 M1 标记物的表达，但增加 M2 标记物的表达。 FTY720可以增强小胶质细胞的吞噬功能。鞘氨醇激酶1/2（SphK1/2）或Sphk2抑制剂可以阻止FTY720改善的M1至M2表型转变，但Sphk1抑制剂未能影响FTY720的作用。此外，Sphk1/2或Sphk2抑制剂促进组蛋白脱乙酰酶（HDAC1）的活性并抑制Krüppel样因子4（KLF4）启动子区域的组蛋白乙酰化，表明核内pFTY720抑制HDAC1激活并阻止KLF4与HDAC1相互作用，从而抑制KLF4脱乙酰化。因此，我们的数据表明，核内SphK2-S1P轴可能促进小胶质细胞极化从M1表型向M2表型的转变，这可能是FTY720预防神经炎症的核内调节机制。
Sphingosine 1-phosphate (S1P) is involved in a variety of cellular responses including microglial activation and polarization. However, the impacts of S1P on ischemia-induced microglial activation and polarization remain unclear. In the present study, Sprague-Dawley rats were selected for middle cerebral artery occlusion (MCAO) establishment and treated with S1P analog FTY720 (0.5, 1, 2 mg/kg) for 24 h. The impacts of FTY720 on oxygen-glucose deprivation (OGD)-induced microglial polarization were examined in the primary cultured microglia. FTY720 treatment could prevent ischemia-induced brain injury and neurological dysfunction, also decrease the levels of IL-1β and TNF-α and promote M2 microglial polarization in rats. Further, we found that FTY720 inhibited the expressions of M1 markers, but increased the expressions of M2 markers in the OGD-insulted microglia. And FTY720 could enhance the phagocytic function of microglia. The sphingosine kinase 1/2 (SphK1/2) or the Sphk2 inhibitor could prevent the M1 to M2 phenotype shift improved by FTY720, but the Sphk1 inhibitor failed to affect the roles of FTY720. Furthermore, the Sphk1/2 or Sphk2 inhibitor promoted the activities of histone deacetylase (HDAC1) and inhibited the histone acetylation of the Krüppel-like factor 4 (KLF4) promoter regions, indicating that intra-nuclear pFTY720 inhibited HDAC1 activations and prevented KLF4 to interact with HDAC1, and thereby suppresses KLF4 deacetylation. Therefore, our data reveals that intra-nuclear SphK2-S1P axis might facilitate the transformation of microglial polarization from M1 to M2 phenotype, which might be intra-nuclear regulatory mechanisms of FTY720-prevented neuroinflammation.