Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1-Dependent M1 Microglial Polarization
Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1-Dependent M1 Microglial Polarization
复制标题
长非编码 RNA H19 通过驱动组蛋白脱乙酰酶 1 依赖性 M1 小胶质细胞极化促进缺血性中风的神经炎症。
DOI：
10.1161/strokeaha.117.017387
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发表时间：
2017-08-01
期刊：
影响因子：
8.3
通讯作者：
Luo, Yumin
中科院分区：
文献类型：
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作者：
Wang, Jue;Zhao, Haiping;Luo, Yumin
背景和目的：长链非编码RNA H19在出生后被抑制，但可被缺氧诱导。我们的目的是调查的影响和潜在的机制H19诱导缺血性stroke. Methods循环H19水平中风患者和小鼠大脑中动脉闭塞进行了评估，使用实时聚合酶链反应。H19 siRNA和组蛋白去乙酰化酶1（HDAC 1）质粒分别用于敲低H19和过表达HDAC 1。大脑中动脉闭塞小鼠和BV 2小胶质细胞进行氧-葡萄糖deprivation.Results-Circulating H19水平显着高于中风患者与健康对照组相比，表明高诊断灵敏度和特异性的小胶质细胞极化和缺血性的结果进行了评估。此外，血浆H19水平与国立卫生研究院卒中量表评分和肿瘤坏死因子-α水平呈正相关。小鼠大脑中动脉闭塞后，血浆、白色血细胞和大脑中的H19水平增加。脑室内注射H19 siRNA可减少梗死体积和脑水肿，降低脑组织和血浆中肿瘤坏死因子-α和白细胞介素-1 β水平，并增加卒中后24小时血浆白细胞介素-10浓度。此外，H19基因敲减可减轻卒中后14天的脑组织损失和神经功能缺损。基于BV 2细胞的实验表明，H19敲低阻断了氧-葡萄糖剥夺驱动的M1小胶质细胞极化，减少了肿瘤坏死因子-α和CD 11b的产生，并增加了Arg-1和CD 206的表达。此外，H19敲低逆转了氧-葡萄糖剥夺诱导的HDAC 1上调和乙酰组蛋白H3和乙酰组蛋白H4下调。相反，HDAC 1过表达否定了H19 knockdown.Conclusions-Our研究结果表明，H19通过驱动HDAC 1依赖的M1小胶质细胞极化促进神经炎症，这表明一种新的基于H19的缺血性卒中的诊断和治疗。
Background and Purpose-Long noncoding RNA H19 is repressed after birth, but can be induced by hypoxia. We aim to investigate the impact on and underlying mechanism of H19 induction after ischemic stroke.Methods-Circulating H19 levels in stroke patients and mice subjected to middle cerebral artery occlusion were assessed using real-time polymerase chain reaction. H19 siRNA and histone deacetylase 1 (HDAC1) plasmid were used to knock down H19 and overexpress HDAC1, respectively. Microglial polarization and ischemic outcomes were assessed in middle cerebral artery occlusion mice and BV2 microglial cells subjected to oxygen-glucose deprivation.Results-Circulating H19 levels were significantly higher in stroke patients compared with healthy controls, indicating high diagnostic sensitivity and specificity. Moreover, plasma H19 levels showed a positive correlation with National Institute of Health Stroke Scale score and tumor necrosis factor-alpha levels. After middle cerebral artery occlusion in mice, H19 levels increased in plasma, white blood cells, and brain. Intracerebroventricular injection of H19 siRNA reduced infarct volume and brain edema, decreased tumor necrosis factor-alpha and interleukin-1 beta levels in brain tissue and plasma, and increased plasma interleukin-10 concentrations 24 hours poststroke. Additionally, H19 knockdown attenuated brain tissue loss and neurological deficits 14 days poststroke. BV2 cell-based experiments showed that H19 knockdown blocked oxygen-glucose deprivation-driven M1 microglial polarization, decreased production of tumor necrosis factor-alpha and CD11b, and increased the expression of Arg-1 and CD206. Furthermore, H19 knockdown reversed oxygen-glucose deprivation-induced upregulation of HDAC1 and downregulation of acetyl-histone H3 and acetyl-histone H4. In contrast, HDAC1 overexpression negated the effects of H19 knockdown.Conclusions-Our findings indicate that H19 promotes neuroinflammation by driving HDAC1-dependent M1 microglial polarization, suggesting a novel H19-based diagnosis and therapy for ischemic stroke.