Folic acid deficiency enhanced microglial immune response via the Notchl/nuclear factor kappa B p65 pathway in hippocampus following rat brain I/R injury and BV2 cells
Folic acid deficiency enhanced microglial immune response via the Notchl/nuclear factor kappa B p65 pathway in hippocampus following rat brain I/R injury and BV2 cells
复制标题
叶酸缺乏通过大鼠脑 I/R 损伤和 BV2 细胞后海马中的 Notch1/核因子 kappa B p65 途径增强小胶质细胞免疫反应
DOI：
10.1111/jcmm.14368
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Zhang, Xumei
中科院分区：
文献类型：
--
作者：
Cheng, Man;Yang, Liu;Zhang, Xumei
近年来的研究发现，叶酸缺乏（艾德）可增加脑缺血后中风的发生率，加重脑损伤。小胶质细胞介导的炎症反应在导致缺血性脑损伤的复杂病理过程中起着至关重要的作用。然而，FD是否参与了实验性脑卒中后小胶质细胞的激活和神经炎症反应，其机制尚不清楚。本研究的目的是评估FD是否调节Notch 1/核因子κ B（NF-κ B）通路，并增强大鼠大脑中动脉闭塞-再灌注（MCAO）模型和氧糖剥夺（OGD）处理的BV-2细胞中的小胶质细胞免疫反应。我们的研究结果表明，FD加重脑缺血/再灌注后海马CA 1，CA 3和齿状回（DG）亚区的神经细胞死亡和夸大的小胶质细胞活化。海马CA 1区对缺血性损伤和艾德治疗更为敏感。促炎细胞因子如肿瘤坏死因子-α、白细胞介素-1 β和白细胞介素-6的蛋白质表达也通过FD治疗在缺血后海马的小胶质细胞和体外OGD应激小胶质细胞模型中增强。此外，艾德不仅显著增强Notch 1和NF-κ B p65的蛋白表达水平，而且还促进plk B α的磷酸化和NF-κ B p65的核转位。用N-[N-（3，5-二氟苯乙酰基）-1-丙氨酰]-S-苯基甘氨酸叔丁酯阻断Notch 1部分减弱了FD处理的缺氧BV-2小胶质细胞中NF-κ B p65的核转位和神经炎性细胞因子的蛋白表达。提示Notch 1/NF-κ B B p65通路介导的小胶质细胞免疫反应可能是艾德治疗加重脑缺血再灌注损伤的分子机制。
Recent studies revealed that folic acid deficiency (ED) increased the likelihood of stroke and aggravated brain injury after focal cerebral ischaemia. The microglia-mediated inflammatory response plays a crucial role in the complicated pathologies that lead to ischaemic brain injury. However, whether FD is involved in the activation of microglia and the neuroinflammation after experimental stroke and the underlying mechanism is still unclear. The aim of the present study was to assess whether FD modulates the Notch1/nuclear factor kappa B (NF-kappa B) pathway and enhances microglial immune response in a rat middle cerebral artery occlusion-reperfusion (MCAO) model and oxygen-glucose deprivation (OGD)-treated BV-2 cells. Our results exhibited that FD worsened neuronal cell death and exaggerated microglia activation in the hippocampal CA1, CA3 and Dentate gyrus (DG) subregions after cerebral ischaemia/reperfusion. The hippocampal CA1 region was more sensitive to ischaemic injury and ED treatment. The protein expressions of proinflammatory cytokines such as tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6 were also augmented by FD treatment in microglial cells of the post-ischaemic hippocampus and in vitro OGD-stressed microglia model. Moreover, ED not only dramatically enhanced the protein expression levels of Notch1 and NF-kappa B p65 but also promoted the phosphorylation of plkB alpha and the nuclear translocation of NF-kappa B p65. Blocking of Notch1 with N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester partly attenuated the nuclear translocation of NF-kappa B p65 and the protein expression of neuroinflammatory cytokines in FD-treated hypoxic BV-2 microglia. These results suggested that Notch1/NF-kappa B p65 pathway-mediated microglial immune response may be a molecular mechanism underlying cerebral ischaemia-reperfusion injury worsened by ED treatment.