Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP+-induced dopaminergic neuronal loss
Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP+-induced dopaminergic neuronal loss
复制标题
转化生长因子-β1 通过 TβR-I 对小胶质细胞起作用，以防止 MPP 诱导的多巴胺能神经元损失
DOI：
10.1016/j.bbi.2015.08.006
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发表时间：
2016-01-01
影响因子：
15.1
通讯作者：
Peng, Yu-Ping
中科院分区：
文献类型：
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作者：
Liu, Zhan;Chen, Hui-Qiao;Peng, Yu-Ping
神经炎症与帕金森病（PD）的发病机制相关，帕金森病是一种以黑质内多巴胺能（DA能）神经元的进行性损失为特征的神经退行性疾病。转化生长因子（TGF）-β 1发挥抗炎和神经保护作用。然而，目前尚不清楚小胶质细胞是否需要TGF-β 1在PD中的神经保护作用。在这里，我们使用shRNA和药理学抑制来确定小胶质细胞TGF-β受体（T β R）-I及其下游信号通路在1-甲基-4-苯基吡啶（MPP+）诱导的DA能神经元毒性中的作用。正如预期的那样，MPP+减少了腹侧中脑细胞培养物中酪氨酸羟化酶（TH）免疫反应细胞的数量。我们发现，MPP+激活小胶质细胞，通过上调CD 11b和诱导型一氧化氮合酶（iNOS）的表达，增加肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1 β的表达和分泌，减少神经营养因子，胰岛素样生长因子（IGF）-1的表达和分泌。TGF-β 1预处理可显著抑制MPP+引起的上述变化。TGF-β 1可上调小胶质细胞T β R-I的表达。小胶质细胞中T β R-I基因的沉默消除了TGF-β 1的神经保护和抗炎特性。TGF-β 1增加小胶质细胞p38 MAPK和Akt磷酸化，这两者分别被p38抑制剂SB 203580和PI 3 K抑制剂LY 294002阻断。用SB 203580或LY 294002预处理小胶质细胞损害了TGF-β 1抑制MPP+诱导的DA能神经元损失和小胶质细胞活化的能力。这些发现证实了TGF-β 1激活小胶质细胞中的T β R-I及其下游p38 MAPK和PI 3 K-Akt信号通路，以防止PD中特有的DA能神经元损失。(C)2015爱思唯尔公司All rights reserved.
Neuroinflammation is associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by a progressive loss of dopaminergic (DAergic) neurons within the substantia nigra. Transforming growth factor (TGF)-beta 1 exerts anti-inflammatory and neuroprotective properties. However, it is unclear if microglia are required for TGF-beta 1 neuroprotection in PD. Here we used both shRNA and pharmacologic inhibition to determine the role of microglial TGF-beta receptor (T beta R)-I and its downstream signaling pathways in 1-methyl-4-phenylpyridinium (MPP+)-induced DAergic neuronal toxicity. As expected, MPP+ reduced the number of tyrosine hydroxylase (TH)-immunoreactive cells in ventral mesencephalic cell cultures. We found that MPP+ activated microglia as determined by an upregulation in expression of CD11b and inducible nitric oxide synthase (iNOS), an increase in expression and secretion of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, and a decrease in expression and secretion of the neurotrophic factor, insulin-like growth factor (IGF)-1. Pretreatment with TGF-beta 1 significantly inhibited all these changes caused by MPP+. Expression of microglial T beta R-I was upregulated by TGF-beta 1. Silencing of the T beta R-I gene in microglia abolished both the neuroprotective and anti-inflammatory properties of TGF-beta 1. TGF-beta 1 increased microglial p38 MAPK and Akt phosphorylation, both of which were blocked by the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, respectively. Pretreatment of microglia with either SB203580 or LY294002 impaired the ability of TGF-beta 1 to inhibit MPP+-induced DAergic neuronal loss and microglial activation. These findings establish that TGF-beta 1 activates T beta R-I and its downstream p38 MAPK and PI3K-Akt signaling pathways in microglia to protect against DAergic neuronal loss that characterizes in PD. (C) 2015 Elsevier Inc. All rights reserved.