IL-1在脑皮质发育不良形成中的作用研究
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摘要
脑皮质发育不良是儿童期难治性癫痫的最常见病因之一。其典型的病理学改变是皮质板层结构紊乱和异形、异位神经元的出现。而导致这些病理改变的根本原因在于大脑皮质板层结构形成过程中出现了异常。神经元迁移是大脑皮质板层结构形成的重要环节，因此神经元的异常迁移是导致脑皮质发育不良的一个重要原因。
目前关于脑皮质发育不良发病机制的研究主要集中在遗传因素，认为特定基因（如Lis1、DCX）的变异是导致脑皮质发育不良的主要原因。但并非所有的脑皮质发育不良患者都存在基因异常，且目前也缺乏公认可靠的基因干预治疗，因此对导致神经元迁移异常的其它因素进行研究，将可能为脑皮质发育不良的防治提供新的策略。
我们课题组前期在炎症与神经元异常迁移领域做了一系列工作，结果显示IL-1β，一种促炎性细胞因子，在严重癫痫发作后神经元的异常迁移中扮演了重要角色，且对离体培养的神经元迁移具有明显的导向作用。这一结果提示IL-1可能参与了脑皮层发育不良中的神经元迁移异常。已有文献报道IL-1在脑皮质发育不良患者的脑组织中呈高表达，但IL-1在脑皮质发育不良形成中的作用，目前未见报道。
目的
本研究拟证实IL-1在发育期大鼠脑内的表达模式；观察下调其功能受体IL1R1的表达对新生神经元迁移及皮质板层结构的影响；进而通过观察放射状胶质的支架结构、新生神经元增殖、神经细胞形态等可能影响神经元迁移的因素来探索IL-1影响神经元迁移的机制；最后对IL-1影响神经迁移可能的分子机制进行初步探讨。
方法
我们通过γ射线过度辐射孕16天的母鼠，建立脑皮质发育不良的动物模型，并以正常发育的仔鼠和正常成年大鼠做为对照；之后，通过RT-PCR及Western检测IL-1β及IL1R1在发育期大脑内的表达；接下来，我们应用RNA干扰（RNAi）结合子宫内胚胎电转（in utero eletroporation, IUE）技术，通过免疫组化及western检测，观察下调IL-1R1表达对新生神经元迁移和皮质板层结构的影响并探索其可能机制；最后，我们通过Transwell实验对IL-1β影响神经迁移可能的分子机制进行了初步的探讨。
结果
1、孕16天的母鼠接受γ射线过度照射后，有10.7%的仔鼠出现自发性抽搐发作，其他仔鼠也表现出不同程度的兴奋性行为，组织病理结果显示模型组动物的板层结构紊乱、皮质变薄，且皮质的II/III层、部分海马的CA2区、CA3区出现结节样结构，提示脑皮质发育不良动物模型构建成功。
2、E17至P7，脑皮质发育不良模型组IL-1β的mRNA水平高于同时期的正常发育仔鼠组及正常成年大鼠组。随着时间的延长，脑皮质发育不良组和正常发育仔鼠组IL-1β的mRNA表达呈下降趋势。直至P28，IL-1β的mRNA表达与正常成年大鼠组相比，无明显差异。进一步研究显示，P0时脑皮质发育不良模型组IL-1β的蛋白表达水平高于同期正常发育仔鼠组合正常成年大鼠组。
IL1R1在各组中的mRNA水平和蛋白水平均有表达，其表达模式与IL-1β类似。随着时间的延长，其mRNA在脑皮质发育不良组和正常发育仔鼠组的表达呈下降趋势，P7时与正常成年大鼠组相比，无明显差异。在蛋白水平上，三组之间的IL1R1的表达在P0时无明显差异。
3、Western结果显示我们成功构建了针对IL1R1的siRNA质粒及人IL1R1的过表达质粒。在E16时，我们采用子宫内胚胎电转技术下调侧脑室神经前体细胞IL1R1的表达，可观察到新生神经元的迁移出现明显异常。本应迁入皮质II/III层的神经元，在P5时，大部分（约为62%）仍停留在室旁区（VZ）、脑室下带（SVZ）和白质（WM）区域。而同时过表达该siRNA序列不能干预的人IL1R1后，这一现象可以得到纠正。大部分细胞（约为84%）仍能正常迁往皮质II/III层。
4、对影响神经元迁移的内外因素进行分析，我们发现下调IL1R1表达后，对板层结构有轻度的影响，但对神经胶质细胞的支架结构、神经细胞增殖、细胞形态等都没有影响，通过Western检测IL-1β的在皮质各层的分布规律，我们发现IL-1β的分布具有明显的阶梯性，提示其可能是通过影响神经元的迁移方向来参与了脑皮质发育不良中神经元的异常迁移。
5、Transwell实验结果显示：下室添加IL-1β对离体培养的神经元胞体的迁移具有明显的吸引作用，而同时添加一定浓度的艰难梭菌毒素B（RhoA信号通路抑制剂）可逆转这种作用。这一结果提示IL-1β可能通过RhoA信号通路参与了脑皮质发育不良中的神经元异常迁移。
结论
各种原因导致的IL-1β在脑皮质发育过程中表达异常，可能通过RhoA信号通路，影响神经元的迁移方向，最终导致脑皮质发育不良的形成。这一结论从炎症后神经元异常迁移的角度阐述了脑皮质发育不良的形成机制，并为脑皮质发育不良的防治提供了新的思路。
Cortical dysplasia (CD) is one of the most common causes in children withrefractory epilepsy. The typical pathological changes in CD are disorders ofcortical plate layer structural and ectopic neurons. Neuronal migration plays animportant role in the formation of lamellar structure in the cortex and aberrantneuronal migration may thus contribute to the development of CD.
A majority of studies aimed to reveal the underlying mechanisms of corticaldysplasia have focused on genetic factors. For example, certain gene mutation,such as Lis1or DCX mutation, may play a crucial role in the formation of CD.However, established gene mutations can not explain the underlying etiology ofall patients with CD. Moreover, there is no such effective gene therapy for CD atpresent. Thus, further investigations of other factors associated with aberrantneuronal migration may provide new clues for the prevention and treatment ofCD.
Our group had focused on the relationship between inflammation andaberrant neuronal migration for a long time. We found that interleukin1beta (IL-1β), which is a pro-inflammatory cytokines, plays an important role in theaberrant neuronal migration after status epilepticus (SE). What’s more, IL-1βplays an attractive effect on the migration of cultured cortical neurons in vitro.These results suggested that IL-1may be involved in aberrant neuronal migrationin CD formation. It had been reported that the expression of IL-1and IL1R1wereelevated in the brain section removed from the CD patients. However, the role ofIL-1in the formation of CD is not clear.
Objectives
The purpose of this study was to confirm the expression pattern of IL-1indeveloping cortex and observe the effect of lamellar structure and neuronalmigration when the IL1R1, the functional receptor of IL-1β,was down-regulated.Then, we investigated the mechanism of IL-1βinvolved in neuronal migrationby observing the effect of radial glia structure, the proliferation of newbornneurons, and the morphology of neural cells when the IL1R1was down-regulated.Finally, the possible downstream signal pathway was discussed.
Methods
We established the animal model of CD by giving overdose gama-irradiationto E16pregnant rats, using the normal pups and normal adult rats as control.RT-PCR and western were used to examine the expression pattern of IL-1βandIL1R1in developing cortex. Specific siRNAs, in utero eletroporation,immunohistology, and western were employed to investigate the effect ofneuronal migration and the possible mechanism. Transwell assay was used toconfirm whether RhoA signal pathway was involved in the downstreammechanism.
Results
1. There were10%pups in CD group underwent the spontaneous seizuresafter their mothers received overdose γ-irradiation at E16. Other pups appearedto be more excited than the normal pups and normal adult rats. The lamellarstructure in the CD group was in chaos and the cortex became thinner than thenormal pups. Neural nodes can be found in the II/III layers, CA2/CA3region insome rats. These results revealed that we established the CD animal modelsuccessfully.
2. The mRNA level of IL-1βin CD was higher than that in normal pups atthe same period, and that in normal adult rats from E17-P7. As time passed by,the expression level of IL-1βdeclined in CD group and normal pups. There wasno significance between CD group and normal adult rats at E28. The westernresults showed that the IL-1βproteinis higher in CD group than that in normalpups and normal adult rats at P0.
IL1R1can be found expressed in all the three groups. The expression patternof IL1R1is similar to IL-1β. As time passed by, the mRNA level of IL-1R1declined in CD group and normal pups. There is no significance of IL1R1mRNAlevel among the three groups at P7. However, unlike IL-1β，the expression ofIL1R1protein has no differences in the three groups.
3. The western results suggested us that the siRNA plasmids andover-expression plasmids of human IL1R1were established successfully. Afterwe down-regulated the expression of IL1R1in neural precursors by in uteroelectroporation，the migration of newborn neurons appeared to be obviouslyabnormal. The newborn neurons should have migrated to the II/III layers incortex at that stage, but most of them (about62%) remained in ventricular zone (VZ)、subventricular zone（SVZ）和white matter（WM）at P5. This phenotypecan be rescued by over human IL1R1plasmids which can not be interfered by thesiRNA sequence。Most of neurons (about84%) can migrate to the II/III layers inthe cortex as usual.
4. We found that down-regulated IL1R1had only slight effect on thelamellar structure，while no effect on the structureof radial glia cells, theproliferation of newborn neurons, and the morphology of neural cells when theIL1R1was down-regulated. After examining the IL-1β expression in differentlayer of cortex by Western, we found that the distribution of IL-1βas a ladderpattern, which suggested that the IL-1β might be involved in the aberrantmigration in CD by affecting the direction of migration.
5. The result of Transwell shows that IL-1βhad an attractive effect on thecortical neurons in vitro, However, clostridium difficile Toxin B(Cdt B), ainhabitator of RhoAsignal pathway, had a negtive effect on the phenotype above.These results suggested that IL-1β may be involved in the aberrant migration inCD by RhoA signal pathway.
Conclusion
Our results indicate that abnormal expression of IL-1β in developing cortexmay affect the direction of neuronal migration through RhoA pathway signalling.This study also suggests that inflammation ralated aberrant neuronal migrationmay be a common cause of CD. The data may provide us new clues for theprevention and treatment of CD.
目前关于脑皮质发育不良发病机制的研究主要集中在遗传因素，认为特定基因（如Lis1、DCX）的变异是导致脑皮质发育不良的主要原因。但并非所有的脑皮质发育不良患者都存在基因异常，且目前也缺乏公认可靠的基因干预治疗，因此对导致神经元迁移异常的其它因素进行研究，将可能为脑皮质发育不良的防治提供新的策略。
我们课题组前期在炎症与神经元异常迁移领域做了一系列工作，结果显示IL-1β，一种促炎性细胞因子，在严重癫痫发作后神经元的异常迁移中扮演了重要角色，且对离体培养的神经元迁移具有明显的导向作用。这一结果提示IL-1可能参与了脑皮层发育不良中的神经元迁移异常。已有文献报道IL-1在脑皮质发育不良患者的脑组织中呈高表达，但IL-1在脑皮质发育不良形成中的作用，目前未见报道。
目的
本研究拟证实IL-1在发育期大鼠脑内的表达模式；观察下调其功能受体IL1R1的表达对新生神经元迁移及皮质板层结构的影响；进而通过观察放射状胶质的支架结构、新生神经元增殖、神经细胞形态等可能影响神经元迁移的因素来探索IL-1影响神经元迁移的机制；最后对IL-1影响神经迁移可能的分子机制进行初步探讨。
方法
我们通过γ射线过度辐射孕16天的母鼠，建立脑皮质发育不良的动物模型，并以正常发育的仔鼠和正常成年大鼠做为对照；之后，通过RT-PCR及Western检测IL-1β及IL1R1在发育期大脑内的表达；接下来，我们应用RNA干扰（RNAi）结合子宫内胚胎电转（in utero eletroporation, IUE）技术，通过免疫组化及western检测，观察下调IL-1R1表达对新生神经元迁移和皮质板层结构的影响并探索其可能机制；最后，我们通过Transwell实验对IL-1β影响神经迁移可能的分子机制进行了初步的探讨。
结果
1、孕16天的母鼠接受γ射线过度照射后，有10.7%的仔鼠出现自发性抽搐发作，其他仔鼠也表现出不同程度的兴奋性行为，组织病理结果显示模型组动物的板层结构紊乱、皮质变薄，且皮质的II/III层、部分海马的CA2区、CA3区出现结节样结构，提示脑皮质发育不良动物模型构建成功。
2、E17至P7，脑皮质发育不良模型组IL-1β的mRNA水平高于同时期的正常发育仔鼠组及正常成年大鼠组。随着时间的延长，脑皮质发育不良组和正常发育仔鼠组IL-1β的mRNA表达呈下降趋势。直至P28，IL-1β的mRNA表达与正常成年大鼠组相比，无明显差异。进一步研究显示，P0时脑皮质发育不良模型组IL-1β的蛋白表达水平高于同期正常发育仔鼠组合正常成年大鼠组。
IL1R1在各组中的mRNA水平和蛋白水平均有表达，其表达模式与IL-1β类似。随着时间的延长，其mRNA在脑皮质发育不良组和正常发育仔鼠组的表达呈下降趋势，P7时与正常成年大鼠组相比，无明显差异。在蛋白水平上，三组之间的IL1R1的表达在P0时无明显差异。
3、Western结果显示我们成功构建了针对IL1R1的siRNA质粒及人IL1R1的过表达质粒。在E16时，我们采用子宫内胚胎电转技术下调侧脑室神经前体细胞IL1R1的表达，可观察到新生神经元的迁移出现明显异常。本应迁入皮质II/III层的神经元，在P5时，大部分（约为62%）仍停留在室旁区（VZ）、脑室下带（SVZ）和白质（WM）区域。而同时过表达该siRNA序列不能干预的人IL1R1后，这一现象可以得到纠正。大部分细胞（约为84%）仍能正常迁往皮质II/III层。
4、对影响神经元迁移的内外因素进行分析，我们发现下调IL1R1表达后，对板层结构有轻度的影响，但对神经胶质细胞的支架结构、神经细胞增殖、细胞形态等都没有影响，通过Western检测IL-1β的在皮质各层的分布规律，我们发现IL-1β的分布具有明显的阶梯性，提示其可能是通过影响神经元的迁移方向来参与了脑皮质发育不良中神经元的异常迁移。
5、Transwell实验结果显示：下室添加IL-1β对离体培养的神经元胞体的迁移具有明显的吸引作用，而同时添加一定浓度的艰难梭菌毒素B（RhoA信号通路抑制剂）可逆转这种作用。这一结果提示IL-1β可能通过RhoA信号通路参与了脑皮质发育不良中的神经元异常迁移。
结论
各种原因导致的IL-1β在脑皮质发育过程中表达异常，可能通过RhoA信号通路，影响神经元的迁移方向，最终导致脑皮质发育不良的形成。这一结论从炎症后神经元异常迁移的角度阐述了脑皮质发育不良的形成机制，并为脑皮质发育不良的防治提供了新的思路。
Cortical dysplasia (CD) is one of the most common causes in children withrefractory epilepsy. The typical pathological changes in CD are disorders ofcortical plate layer structural and ectopic neurons. Neuronal migration plays animportant role in the formation of lamellar structure in the cortex and aberrantneuronal migration may thus contribute to the development of CD.
A majority of studies aimed to reveal the underlying mechanisms of corticaldysplasia have focused on genetic factors. For example, certain gene mutation,such as Lis1or DCX mutation, may play a crucial role in the formation of CD.However, established gene mutations can not explain the underlying etiology ofall patients with CD. Moreover, there is no such effective gene therapy for CD atpresent. Thus, further investigations of other factors associated with aberrantneuronal migration may provide new clues for the prevention and treatment ofCD.
Our group had focused on the relationship between inflammation andaberrant neuronal migration for a long time. We found that interleukin1beta (IL-1β), which is a pro-inflammatory cytokines, plays an important role in theaberrant neuronal migration after status epilepticus (SE). What’s more, IL-1βplays an attractive effect on the migration of cultured cortical neurons in vitro.These results suggested that IL-1may be involved in aberrant neuronal migrationin CD formation. It had been reported that the expression of IL-1and IL1R1wereelevated in the brain section removed from the CD patients. However, the role ofIL-1in the formation of CD is not clear.
Objectives
The purpose of this study was to confirm the expression pattern of IL-1indeveloping cortex and observe the effect of lamellar structure and neuronalmigration when the IL1R1, the functional receptor of IL-1β,was down-regulated.Then, we investigated the mechanism of IL-1βinvolved in neuronal migrationby observing the effect of radial glia structure, the proliferation of newbornneurons, and the morphology of neural cells when the IL1R1was down-regulated.Finally, the possible downstream signal pathway was discussed.
Methods
We established the animal model of CD by giving overdose gama-irradiationto E16pregnant rats, using the normal pups and normal adult rats as control.RT-PCR and western were used to examine the expression pattern of IL-1βandIL1R1in developing cortex. Specific siRNAs, in utero eletroporation,immunohistology, and western were employed to investigate the effect ofneuronal migration and the possible mechanism. Transwell assay was used toconfirm whether RhoA signal pathway was involved in the downstreammechanism.
Results
1. There were10%pups in CD group underwent the spontaneous seizuresafter their mothers received overdose γ-irradiation at E16. Other pups appearedto be more excited than the normal pups and normal adult rats. The lamellarstructure in the CD group was in chaos and the cortex became thinner than thenormal pups. Neural nodes can be found in the II/III layers, CA2/CA3region insome rats. These results revealed that we established the CD animal modelsuccessfully.
2. The mRNA level of IL-1βin CD was higher than that in normal pups atthe same period, and that in normal adult rats from E17-P7. As time passed by,the expression level of IL-1βdeclined in CD group and normal pups. There wasno significance between CD group and normal adult rats at E28. The westernresults showed that the IL-1βproteinis higher in CD group than that in normalpups and normal adult rats at P0.
IL1R1can be found expressed in all the three groups. The expression patternof IL1R1is similar to IL-1β. As time passed by, the mRNA level of IL-1R1declined in CD group and normal pups. There is no significance of IL1R1mRNAlevel among the three groups at P7. However, unlike IL-1β，the expression ofIL1R1protein has no differences in the three groups.
3. The western results suggested us that the siRNA plasmids andover-expression plasmids of human IL1R1were established successfully. Afterwe down-regulated the expression of IL1R1in neural precursors by in uteroelectroporation，the migration of newborn neurons appeared to be obviouslyabnormal. The newborn neurons should have migrated to the II/III layers incortex at that stage, but most of them (about62%) remained in ventricular zone (VZ)、subventricular zone（SVZ）和white matter（WM）at P5. This phenotypecan be rescued by over human IL1R1plasmids which can not be interfered by thesiRNA sequence。Most of neurons (about84%) can migrate to the II/III layers inthe cortex as usual.
4. We found that down-regulated IL1R1had only slight effect on thelamellar structure，while no effect on the structureof radial glia cells, theproliferation of newborn neurons, and the morphology of neural cells when theIL1R1was down-regulated. After examining the IL-1β expression in differentlayer of cortex by Western, we found that the distribution of IL-1βas a ladderpattern, which suggested that the IL-1β might be involved in the aberrantmigration in CD by affecting the direction of migration.
5. The result of Transwell shows that IL-1βhad an attractive effect on thecortical neurons in vitro, However, clostridium difficile Toxin B(Cdt B), ainhabitator of RhoAsignal pathway, had a negtive effect on the phenotype above.These results suggested that IL-1β may be involved in the aberrant migration inCD by RhoA signal pathway.
Conclusion
Our results indicate that abnormal expression of IL-1β in developing cortexmay affect the direction of neuronal migration through RhoA pathway signalling.This study also suggests that inflammation ralated aberrant neuronal migrationmay be a common cause of CD. The data may provide us new clues for theprevention and treatment of CD.
引文
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