小胶质细胞表达钾离子通道Kv1.2及其对细胞因子和活性氧生成的调控作用
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摘要
小胶质细胞是中枢神经系统的“感受器”,当脑内微环境发生变化时它首先被激活,活化后的小胶质细胞通过释放细胞因子和活性氧(Reactive OxygenSpecies,ROS)等对周围环境进行调整;此时其膜电生理学特性的改变对其生物学行为起到调控作用;小胶质细胞表达多种离子通道,它们协调运转控制着小胶质细胞膜的生物学特性。业已证实小胶质细胞表达电压依从性钾离子通道(Voltage gated potassium channel,Kv),它们所控制的外向延迟整合钾离子电流是小胶质细胞活化的特征,其开放所致的细胞内钾离子浓度降低是上调细胞因子表达的关键步骤。研究表明小胶质细胞表达Kv1.3、Kv1.5,它们与小胶质细胞的增殖、迁移、释放细胞因子和ROS等多种生理功能有关;使用这些通道的阻断剂能够降低小胶质细胞活化的程度,减轻神经元损伤。因此深入研究小胶质细胞膜上Kv的表达及其可能的功能,对阐明小胶质细胞活化的分子机制,寻找调控其活化的靶点具有重要意义。目的:本研究旨在探索钾离子通道Kv1.2在小胶质细胞的表达及其可能的功能。方法:采用免疫荧光双重标记法观察大鼠不同发育阶段脑内阿米巴状小胶质细胞表达Kv1.2的情况;并通过免疫荧光双重标记和real time PCR技术,观察体外培养的小胶质细胞Kv1.2表达的情况。体内建立大鼠缺氧动物模型,观察不同年龄大鼠缺氧后小胶质细胞表达Kv1.2的变化;体外采用脂多糖(Lipopolysaccharide,LPS)、缺氧(Hypoxia exposure,HPE)、三磷酸腺苷(Adenosine 5'-triphosphate,ATP)诱导激活小胶质细胞,通过real time PCR观察小胶质细胞Kv1.2、白细胞介素1β(Interleukin-1β,IL-1β)和肿瘤坏死因子(Tumornecrosis factor,TNFα)mRNA表达的变化;并采用特异性结合钾离子的荧光探针(Potassium-binding benzofuran isophthalate acetoxymethyl ester,PBFI AM)作为标记物,检测小胶质激活后细胞内钾离子浓度的变化。最后,当小胶质细胞被LPS、HPE、ATP诱导激活之后,使用东亚钳蝎毒提取物(rTityustoxin-Kα,TsTx)阻断Kv1.2通道再次观察上述指标的变化;并用LPS激活细胞以及TsTx阻断通道后通过流式细胞仪观察小胶质细胞内ROS产生的改变。结果:体内外小胶质细胞均表达Kv1.2;体内Kv1.2的表达伴随发育过程出现变化,P1-10大鼠脑内阿米巴状小胶质细胞表达Kv1.2,P14开始Kv1.2的表达出现下调,P21的大鼠脑内突起型小胶质细胞几乎不能观察到Kv1.2的表达。P1大鼠缺氧后小胶质细胞表达Kv1.2显著增加;体外real time PCR分析的结果亦证实,当细胞被LPS、缺氧、ATP诱导后Kv1.2 mRNA的表达出现上调;同时小胶质细胞表达IL-1β、TNFα增加;并伴随细胞内钾离子浓度降低。通过TsTx特异性阻断Kv1.2通道电流后,细胞内钾离子浓度出现恢复,同时使得LPS、缺氧、ATP诱导细胞后的IL-1β和TNFα的表达降低,LPS诱导的小胶质细胞ROS产生出现减少。结论:①本研究首次证实小胶质细胞表达Kv1.2,并随动物发育而逐渐消失,提示Kv1.2的表达与发育早期动物脑内的微环境需求有关。②Kv1.2的表达参与了小胶质细胞活化的过程。③Kv1.2的表达在LPS诱导的ROS生成中具有重要作用。④缺氧后小胶质细胞释放IL-1β和TNFα增多可能因缺氧后小胶质细胞表达Kv1.2上调,钾离子外流增多,细胞内钾离子浓度降低所致。⑤Kv1.2的表达在ATP激活小胶质细胞的过程中发挥作用。⑥Kv1.2通道的特异阻断剂TsTx使得小胶质细胞的活化程度减轻。因此,进一步研究该通道的功能,优化该通道阻断剂TsTx的剂量,阻断该通道电流,能够为控制因小胶质细胞过度活化而引起的炎症反应提供有力的实验室证据。
[Abstract]Objective:Microglial cells monitor the state of health of the surrounding tissues in the central nervous system and act as a neuropathology sensor.They are responsive to various stimuli including infections and ischemia and are activated in some dieases.Microglial cells are endowed with different potassium ion channels but their expression and involvement in specific functions has remained to be fully explored.In this connection,ion channels that modulate the membrane potential control the electrophysiological characteristic of microglia.A fuller understanding of the ion channels is therefore vital in elucidating the mechanism of microglial activation.Method:Immunohistochemistry for Kv1.2 was carried out using the ABC method.Double immunofluorescence labeling for Kv1.2 and OX42/Lectin(The mark of microglia)was used to determine the Kv1.2 cellular location.P1 postnatal rats were kept in a chamber filled with a gas mixture of 5%oxygen and 95%nitrogen for 3 hours.Quantitative RT-PCR was carried out on a Light Cycler 3 instrument to analysis the IL-1βand TNFαmRNA expression.Intracellular levels of potassium were assessed by determination of PBFI fluorescence.In order to confirm that the changes in intracellular potassium concentration and release of cytokines by microglial cells under different conditions involved Kv1.2,TsTx,a specific and a potent Kv1.2 current blocker were applied to the cells in culture.Results:This study has shown Kv1.2 expression in the amoeboid microglia in the postnatal rats' brain between P1 and P10 days.At P14,Kv1.2 expression was localized in the ramified microglia and at P21,it was hardly detected.In P1 rats exposed to hypoxia,Kv1.2 immunoreactivity in amoeboid microglia was markedly enhanced.RT-PCR analysis confirmed Kv1.2 mRNA expression in microglial cell culture and murine BV-2 cells. Furthermore,it was up-regulated when the cells were subjected to hypoxia. Additionally,Kv1.2 mRNA expression coupled by that of IL-1βand TNF-αincreased following ATP,and LPS application.Concomitantly,the intracellular potassium concentration in activated microglia as determined by PBFI fluorescence decreased. Blockade of Kv1.2 channel with TsTx resulted in partial recovery of intracellular potassium concentration accompanied by a reduced expression of IL-1βand TNF-αas well as production of intracellular ROS.Conclusion:Kv1.2 expression change is related to the specific necessary of microglia during rat developing.Its expression increase related to the microglia activation.We conclude that Kv1.2 in microglia is sensitive to hypoxia,ATP and LPS.Its up-regulated expression as elicited by the external stimuli may be linked to IL-1βand TNFαexpression and ROS production. Hence,optimizing the dosage of TsTx in suppression of Kv1.2 function may be a potential therapeutic means in ameliorating neuroinflammation in which microglial activation is implicated.
[Abstract]Objective:Microglial cells monitor the state of health of the surrounding tissues in the central nervous system and act as a neuropathology sensor.They are responsive to various stimuli including infections and ischemia and are activated in some dieases.Microglial cells are endowed with different potassium ion channels but their expression and involvement in specific functions has remained to be fully explored.In this connection,ion channels that modulate the membrane potential control the electrophysiological characteristic of microglia.A fuller understanding of the ion channels is therefore vital in elucidating the mechanism of microglial activation.Method:Immunohistochemistry for Kv1.2 was carried out using the ABC method.Double immunofluorescence labeling for Kv1.2 and OX42/Lectin(The mark of microglia)was used to determine the Kv1.2 cellular location.P1 postnatal rats were kept in a chamber filled with a gas mixture of 5%oxygen and 95%nitrogen for 3 hours.Quantitative RT-PCR was carried out on a Light Cycler 3 instrument to analysis the IL-1βand TNFαmRNA expression.Intracellular levels of potassium were assessed by determination of PBFI fluorescence.In order to confirm that the changes in intracellular potassium concentration and release of cytokines by microglial cells under different conditions involved Kv1.2,TsTx,a specific and a potent Kv1.2 current blocker were applied to the cells in culture.Results:This study has shown Kv1.2 expression in the amoeboid microglia in the postnatal rats' brain between P1 and P10 days.At P14,Kv1.2 expression was localized in the ramified microglia and at P21,it was hardly detected.In P1 rats exposed to hypoxia,Kv1.2 immunoreactivity in amoeboid microglia was markedly enhanced.RT-PCR analysis confirmed Kv1.2 mRNA expression in microglial cell culture and murine BV-2 cells. Furthermore,it was up-regulated when the cells were subjected to hypoxia. Additionally,Kv1.2 mRNA expression coupled by that of IL-1βand TNF-αincreased following ATP,and LPS application.Concomitantly,the intracellular potassium concentration in activated microglia as determined by PBFI fluorescence decreased. Blockade of Kv1.2 channel with TsTx resulted in partial recovery of intracellular potassium concentration accompanied by a reduced expression of IL-1βand TNF-αas well as production of intracellular ROS.Conclusion:Kv1.2 expression change is related to the specific necessary of microglia during rat developing.Its expression increase related to the microglia activation.We conclude that Kv1.2 in microglia is sensitive to hypoxia,ATP and LPS.Its up-regulated expression as elicited by the external stimuli may be linked to IL-1βand TNFαexpression and ROS production. Hence,optimizing the dosage of TsTx in suppression of Kv1.2 function may be a potential therapeutic means in ameliorating neuroinflammation in which microglial activation is implicated.
引文
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