DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage
DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage
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DHEA 在实验性蛛网膜下腔出血中通过诱导 JMJD3 减弱小胶质细胞活化。
DOI：
10.1186/s12974-019-1641-y
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发表时间：
2019-11-28
影响因子：
9.3
通讯作者：
Hang, Chun-Hua
中科院分区：
文献类型：
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作者：
Tao, Tao;Liu, Guang-Jie;Hang, Chun-Hua
背景小胶质细胞是中枢神经系统中的常驻免疫细胞，也是先天免疫系统的核心。蛛网膜下腔出血（SAH）后小胶质细胞的过度激活在很大程度上导致早期脑损伤，从而导致不良预后。脱氢表雄酮（DHEA）是一种大脑中富含的类固醇激素，最近被发现可以调节小胶质细胞的激活。本研究的目的是探讨 DHEA 在 SAH 中的作用。方法我们使用血管内穿孔的体内模型和血红蛋白暴露的体外模型来说明 DHEA 对 SAH 中小胶质细胞的影响。结果在实验性 SAH 小鼠中，外源性 DHEA 给药增加了大脑中 DHEA 的水平并调节了小胶质细胞的活化。在用 DHEA 预处理的 SAH 小鼠中也观察到神经元损伤的改善和神经学结果的改善，表明 DHEA 的神经元保护作用。在培养的小胶质细胞中，接触血红蛋白后，DHEA 升高 Jumonji d3（JMJD3，组蛋白 3 去甲基酶）的 mRNA 和蛋白水平，下调 H3K27me3 水平，并抑制促炎基因的转录。 DHEA 也减弱了小胶质细胞介导的对初级神经元的破坏性促炎作用。然而，JMJD3 的特异性抑制消除了 DHEA 的保护作用。接下来我们验证了 DHEA 诱导的 JMJD3 表达，至少部分是通过原肌球蛋白相关激酶 A (TrkA)/Akt 信号通路。结论 DHEA 在 SAH 后具有神经保护作用。此外，DHEA 增加小胶质细胞 JMJD3 的表达，以调节血红蛋白暴露后促炎/抗炎小胶质细胞的激活，从而抑制炎症。
BackgroundMicroglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH.MethodsWe used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH.ResultsIn experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway.ConclusionsDHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.