IL-1β和TNF-α对原代培养的腹侧中脑神经元铁代谢的调控机制研究
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摘要
帕金森病(Parkinson's disease, PD)是一种常见的中枢神经系统退行性疾病,临床表现主要有静止性震颤、肌僵直和运动减少等症状。其主要病理学基础为黑质(substantia nigra, SN)多巴胺(dopamine, DA)能神经元的脱失以及继发引起的纹状体DA含量下降。迄今为止,PD的发病原因仍未完全明了,遗传、环境、年龄因素导致的如神经炎症、铁代谢异常、线粒体功能障碍、蛋白异常聚集等都被认为参加了PD的发病。神经炎症反应主要表现为小胶质细胞的激活和炎性因子如白细胞介素1β(interleukin 1β,IL-1β)和肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)的大量释放。尸检结果和动物实验证实在PD病人和动物模型的SN和纹状体区域IL-1β和TNF-α的含量升高；将IL-1β和TNF-α直接注射至脑内可以引起DA能神经元的凋亡,而阻断IL-1β和TNF-α的受体可以缓解6-羟基多巴胺(6-hydroxydopamine,6-OHDA)和1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, MPTP)制备的PD动物模型脑内DA能神经元的损伤。这些证据提示炎性因子可能参与了DA能神经元的损伤。在PD病人脑内炎性因子升高的SN区同时存在铁的异常聚积,而神经炎症反应与铁聚积之间的关系却并未引起人们足够的重视。本实验应用流式细胞仪技术、免疫荧光、免疫印迹、酶联免疫吸附实验、激光共聚焦扫描技术等多项研究方法,观察了激活的小胶质细胞释放的IL-1β和TNF-α是否可以影响腹侧中脑(ventral mesencephalon, VM)神经元的铁代谢,并对其调控机制进行了探讨。结果如下：
1、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h,细胞的摄铁功能显著增强(P<0.01),铁转出功能显著降低(P<0.01)。
2、10ng/ml的IL-1p和TNF-α处理原代培养的VM神经元24h,含有铁反应元件(iron responsive element, IRE)的二价金属离子转运体(divalent metal transporter 1, DMT1)的蛋白和mRNA水平都有显著增高(P<0.05),铁转出蛋白ferroportin1 (FPN1)的蛋白和mRNA的表达水平都有显著降低(P<0.05)。
3、10 n∥ml的IL-1p和TNF-α处理原代培养的VM神经元24h,铁调节蛋白1 (iron regulatory protein, IRP1)的蛋白表达水平有显著增高(P<0.05)。
4、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h,细胞内活性氧物质(reactive oxide species, ROS)和一氧化氮(nitric oxide, NO)的生成显著增加(P<0.01)。
5、0.5 mmol/L的抗氧化剂N-乙酰-L-半胱氨酸(N-acetyl-1-cysteine, NAC)和1 mmol/L的一氧化氮合成酶抑制剂Nω-硝基-L-精氨酸甲酯盐酸盐(Nω-Nitro-L-arginine methyl ester hydrochloride, L-NAME)预处理0.5h后,可分别阻断IL-1β引起的ROS和NO的生成,进而阻断神经元内IRP1的表达上调,TNF-α处理组得到同样的结果。
6、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h, hepcidin的mRNA水平显著升高(P<0.05)。
7、800ng/ml的脂多糖(lipopolysaccharide, LPS)处理原代培养的小胶质细胞48h,IL-1β和TNF-α的释放量显著增加(P<0.01)。100μm/L的枸橼酸铁铵(ferric ammonium citrate, FAC)预处理可显著增加其释放量(P<0.05),而100μm/L甲磺酸去铁胺(desferrioxamine mesylate, DFO)预处理则显著减少其释放量(P<0.05)。
上述结果表明,炎性因子IL-1p和TNF-α能激活VM神经元的IRP1,进而引起DMT1+IRE的上调和FPN1的下调,从而增强细胞的摄铁功能并减弱细胞的铁转出功能。IRP1的激活可能与细胞内ROS和NO的生成有直接关系,抗氧化剂NAC和一氧化氮合酶抑制剂L-NAME可以完全阻断IRP1的激活IL-1β和TNF-α诱导的hepcidin上调也参与了FPN1的表达下调,加剧了神经元内的铁聚积。脂多糖诱导的小胶质细胞激活可释放大量的IL-1p和TNF-α,并且这一过程可以被细胞内的高铁状态所增强,而被铁缺乏状态所减弱。本实验证实了体外培养的小胶质细胞释放的IL-1p和TNF-α可以调控VM神经元铁的转运,进而导致细胞内的铁聚集和细胞损伤。本研究首次证实了小胶质细胞可通过释放炎性因子而影响神经元的铁代谢,从而为PD中神经炎症和铁代谢异常之间的相互作用以及二者对DA能神经元的损伤提供了强有力的实验基础,并为PD的临床抗炎治疗提供更加详实的理论依据。
Parkinson's disease (PD) is a common neurodegenerative disorder characterized symptomatically by resting tremor, rigidity, and bradykinesia. The neuropathological hallmarks of PD include the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the subsequent depletion of dopamine in the striatum. Although the pathogenesis of PD is still unclear up to now, neuroinflammation, abnormal iron deposit, protein aggregation or mitochondria dysfunction related to environmental, heredity factors or aging were reported to be involved in PD pathogenesis. The prominent hallmarks of neuroinflammation is microglia activation and subsequent secretion of pro-inflammatory cytokines such as interleukin 1β(IL-1β) and tumour necrosis factor-a (TNF-a). Elevated cytokines IL-1βand TNF-a has been detected in the SN and striatum of PD patients and animal models. Direct intra-parenchymal injection of TNF-a and IL-1βinduced dopaminergic neurons degeneration; while blockage of the IL-1βor TNF-a receptor attenuate the death of dopaminergic neurons in 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) induced PD models. Although the mechanisms underlying elevated cytokines induced neurotoxicity are not fully elucidated, PD patients showed amplified levels of pro-inflammatory cytokines in the SN, the same region where iron deposit occured. The relationship between neuroinflammation and iron accumulation becomes compelling. Using fluorometric assays, immunofluorescence, enzyme-linked immunoabsorbent assay, laser confocal scanning microscopy and other methods, the present study aimed to investigate whether and how the pro-inflammatory cytokines IL-1βand TNF-a released by activated microglia, can affect the iron metabolism of ventral mesencephalic (VM) neurons. The results were as follows:
1. Iron influx was increased (P<0.01) and iron efflux was decreased (P<0.01) in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h.
2. Divalent metal transporter 1 with the iron response element (DMT1+IRE) was up-regulated on both protein and mRNA levels (P<0.05), and ferroportinl (FPN1) was down-regulated on both protein and mRNA levels (P<0.05) in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h.
3. Iron regulatory protein (IRP) 1 protein level was up-regulated in primary VM neurons with 10 ng/ml IL-1(3 or TNF-a treatment for 24 h (P<0.05).
4. Reactive oxide species (ROS) and nitric oxide (NO) generation was enhanced in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h (P<0.01).
5. IL-1βand TNF-a induced IRP1 activation was fully abolished in primary VM neurons by pretreatment with 0.5 mmol/L N-acetyl-1-cysteine (NAC) and 1 mmol/L Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) due to the complete blockage ROS and NO generation.
6. Hepcidin mRNA expression was increased in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h (P<0.05).
7. IL-1βand TNF-a release was significantly increased in primary microglia with 800 ng/ml lipopolysaccharide (LPS) treatment for 48 h (P<0.01), and this process was enhanced by 100μm/L ferric ammonium citrate (FAC) (P<0.05), but attenuated by 100μm/L desferrioxamine mesylate (DFO) (P<0.05).
The above results suggest that IL-1βand TNF-a can induce activation of IRP1, thus up-regulated DMT1+IRE expression and down-regulated FPN1 expression, which are responsible for the increased iron influx and decreased iron efflux of VM neurons. ROS and NO may be responsible for the activation of IRP1; which was fully abolished by co-administration of radical scavenger NAC and nitric oxide synthase inhibitor L-NAME. In addition to IRP1, hepcidin also participate in down-regulation of FPN1. And microglia can be activated by LPS, resulting in abundant IL-1(3 and TNF-a secretion. This process is enhanced by iron repletion and attenuated by iron depletion. Our findings provide evidence that microglia play an important role in neuron iron homoeostasis by secreting IL-1(3 and TNF-a. Oxidative stress and NO induced by IL-1β and TNF-a activated IRP1, which regulated expression of DMTl+IRE and FPN1, thus leading to neuron iron load and even demise. Our findings provide powerful evidence that the cooperative effect of neuroinflammation and iron metabolism may enhance dopaminergic neurons demise in PD and further support that anti-inflammation could be valuable therapeutic approaches in PD.
1、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h,细胞的摄铁功能显著增强(P<0.01),铁转出功能显著降低(P<0.01)。
2、10ng/ml的IL-1p和TNF-α处理原代培养的VM神经元24h,含有铁反应元件(iron responsive element, IRE)的二价金属离子转运体(divalent metal transporter 1, DMT1)的蛋白和mRNA水平都有显著增高(P<0.05),铁转出蛋白ferroportin1 (FPN1)的蛋白和mRNA的表达水平都有显著降低(P<0.05)。
3、10 n∥ml的IL-1p和TNF-α处理原代培养的VM神经元24h,铁调节蛋白1 (iron regulatory protein, IRP1)的蛋白表达水平有显著增高(P<0.05)。
4、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h,细胞内活性氧物质(reactive oxide species, ROS)和一氧化氮(nitric oxide, NO)的生成显著增加(P<0.01)。
5、0.5 mmol/L的抗氧化剂N-乙酰-L-半胱氨酸(N-acetyl-1-cysteine, NAC)和1 mmol/L的一氧化氮合成酶抑制剂Nω-硝基-L-精氨酸甲酯盐酸盐(Nω-Nitro-L-arginine methyl ester hydrochloride, L-NAME)预处理0.5h后,可分别阻断IL-1β引起的ROS和NO的生成,进而阻断神经元内IRP1的表达上调,TNF-α处理组得到同样的结果。
6、10ng/ml的IL-1β和TNF-α处理原代培养的VM神经元24h, hepcidin的mRNA水平显著升高(P<0.05)。
7、800ng/ml的脂多糖(lipopolysaccharide, LPS)处理原代培养的小胶质细胞48h,IL-1β和TNF-α的释放量显著增加(P<0.01)。100μm/L的枸橼酸铁铵(ferric ammonium citrate, FAC)预处理可显著增加其释放量(P<0.05),而100μm/L甲磺酸去铁胺(desferrioxamine mesylate, DFO)预处理则显著减少其释放量(P<0.05)。
上述结果表明,炎性因子IL-1p和TNF-α能激活VM神经元的IRP1,进而引起DMT1+IRE的上调和FPN1的下调,从而增强细胞的摄铁功能并减弱细胞的铁转出功能。IRP1的激活可能与细胞内ROS和NO的生成有直接关系,抗氧化剂NAC和一氧化氮合酶抑制剂L-NAME可以完全阻断IRP1的激活IL-1β和TNF-α诱导的hepcidin上调也参与了FPN1的表达下调,加剧了神经元内的铁聚积。脂多糖诱导的小胶质细胞激活可释放大量的IL-1p和TNF-α,并且这一过程可以被细胞内的高铁状态所增强,而被铁缺乏状态所减弱。本实验证实了体外培养的小胶质细胞释放的IL-1p和TNF-α可以调控VM神经元铁的转运,进而导致细胞内的铁聚集和细胞损伤。本研究首次证实了小胶质细胞可通过释放炎性因子而影响神经元的铁代谢,从而为PD中神经炎症和铁代谢异常之间的相互作用以及二者对DA能神经元的损伤提供了强有力的实验基础,并为PD的临床抗炎治疗提供更加详实的理论依据。
Parkinson's disease (PD) is a common neurodegenerative disorder characterized symptomatically by resting tremor, rigidity, and bradykinesia. The neuropathological hallmarks of PD include the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the subsequent depletion of dopamine in the striatum. Although the pathogenesis of PD is still unclear up to now, neuroinflammation, abnormal iron deposit, protein aggregation or mitochondria dysfunction related to environmental, heredity factors or aging were reported to be involved in PD pathogenesis. The prominent hallmarks of neuroinflammation is microglia activation and subsequent secretion of pro-inflammatory cytokines such as interleukin 1β(IL-1β) and tumour necrosis factor-a (TNF-a). Elevated cytokines IL-1βand TNF-a has been detected in the SN and striatum of PD patients and animal models. Direct intra-parenchymal injection of TNF-a and IL-1βinduced dopaminergic neurons degeneration; while blockage of the IL-1βor TNF-a receptor attenuate the death of dopaminergic neurons in 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) induced PD models. Although the mechanisms underlying elevated cytokines induced neurotoxicity are not fully elucidated, PD patients showed amplified levels of pro-inflammatory cytokines in the SN, the same region where iron deposit occured. The relationship between neuroinflammation and iron accumulation becomes compelling. Using fluorometric assays, immunofluorescence, enzyme-linked immunoabsorbent assay, laser confocal scanning microscopy and other methods, the present study aimed to investigate whether and how the pro-inflammatory cytokines IL-1βand TNF-a released by activated microglia, can affect the iron metabolism of ventral mesencephalic (VM) neurons. The results were as follows:
1. Iron influx was increased (P<0.01) and iron efflux was decreased (P<0.01) in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h.
2. Divalent metal transporter 1 with the iron response element (DMT1+IRE) was up-regulated on both protein and mRNA levels (P<0.05), and ferroportinl (FPN1) was down-regulated on both protein and mRNA levels (P<0.05) in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h.
3. Iron regulatory protein (IRP) 1 protein level was up-regulated in primary VM neurons with 10 ng/ml IL-1(3 or TNF-a treatment for 24 h (P<0.05).
4. Reactive oxide species (ROS) and nitric oxide (NO) generation was enhanced in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h (P<0.01).
5. IL-1βand TNF-a induced IRP1 activation was fully abolished in primary VM neurons by pretreatment with 0.5 mmol/L N-acetyl-1-cysteine (NAC) and 1 mmol/L Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) due to the complete blockage ROS and NO generation.
6. Hepcidin mRNA expression was increased in primary VM neurons with 10 ng/ml IL-1βor TNF-a treatment for 24 h (P<0.05).
7. IL-1βand TNF-a release was significantly increased in primary microglia with 800 ng/ml lipopolysaccharide (LPS) treatment for 48 h (P<0.01), and this process was enhanced by 100μm/L ferric ammonium citrate (FAC) (P<0.05), but attenuated by 100μm/L desferrioxamine mesylate (DFO) (P<0.05).
The above results suggest that IL-1βand TNF-a can induce activation of IRP1, thus up-regulated DMT1+IRE expression and down-regulated FPN1 expression, which are responsible for the increased iron influx and decreased iron efflux of VM neurons. ROS and NO may be responsible for the activation of IRP1; which was fully abolished by co-administration of radical scavenger NAC and nitric oxide synthase inhibitor L-NAME. In addition to IRP1, hepcidin also participate in down-regulation of FPN1. And microglia can be activated by LPS, resulting in abundant IL-1(3 and TNF-a secretion. This process is enhanced by iron repletion and attenuated by iron depletion. Our findings provide evidence that microglia play an important role in neuron iron homoeostasis by secreting IL-1(3 and TNF-a. Oxidative stress and NO induced by IL-1β and TNF-a activated IRP1, which regulated expression of DMTl+IRE and FPN1, thus leading to neuron iron load and even demise. Our findings provide powerful evidence that the cooperative effect of neuroinflammation and iron metabolism may enhance dopaminergic neurons demise in PD and further support that anti-inflammation could be valuable therapeutic approaches in PD.
引文
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