TGF1 inhibits IFN-mediated microglia activation and protects mDA neurons from IFN-driven neurotoxicity
TGF1 inhibits IFN-mediated microglia activation and protects mDA neurons from IFN-driven neurotoxicity
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DOI：
10.1111/jnc.13111
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发表时间：
2015-07-01
影响因子：
4.7
通讯作者：
Spittau, Bjoern
中科院分区：
文献类型：
--
作者：
Zhou, Xiaolai;Zoeller, Tanja;Spittau, Bjoern
小胶质细胞介导的神经炎症已被报道为家族性和散发性形式的帕金森病（PD）的共同特征，并且越来越多的证据表明PD的发作和进展与涉及干扰素（IFN）的神经炎症反应的程度相关。转化生长因子1（TGF-1）已被证明是一个主要的球员在调节小胶质细胞的活化状态和功能，因此，可能是一个潜在的治疗剂，通过塑造小胶质细胞的活化表型过程中的神经退行性疾病，如PD。在这项研究中，我们证明了TGF-1能够通过减弱STAT 1磷酸化和IFNR表达来阻断IFN诱导的小胶质细胞活化。此外，我们确定了一组参与小胶质细胞IFN信号转导的基因，这些基因在TGF-1治疗后显著下调，导致小胶质细胞对IFN刺激的敏感性降低。有趣的是，介导IFN信号负调控的基因，如SOCS 2和SOCS 6，在TGF 1处理后上调。最后，我们证明，TGF-1是能够保护中脑多巴胺能（MDA）神经元从IFN-驱动的神经毒性在混合神经元胶质细胞文化来自胚胎第14天（E14）中脑组织。总之，这些数据强调了TGF-1作为小胶质细胞的关键免疫调节因子的重要性，通过沉默IFN-介导的小胶质细胞活化，从而从IFN-诱导的神经毒性中拯救mDA神经元。干扰素（IFN）是一种有效的促炎因子，其触发小胶质细胞的活化和随后的神经毒性因子的释放。转化生长因子1（Transforming growth factor 1，TGF 1）能够抑制干扰素介导的小胶质细胞活化，其特征是释放一氧化氮（nitric oxide，NO）和肿瘤坏死因子（tumor necrosis factor，TNF）。通过降低IFN诱导基因以及信号受体IFNR 1的表达，TGF 1降低了小胶质细胞对IFN的反应性。在混合神经元-胶质细胞培养中，TGF-1保护中脑多巴胺能（mDA）神经元免受IFN诱导的神经毒性。
Microglia-mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinsons disease (PD), and a growing body of evidence indicates that onset and progression of PD correlates with the extent of neuroinflammatory responses involving Interferon (IFN). Transforming growth factor 1 (TGF1) has been shown to be a major player in the regulation of microglia activation states and functions and, thus, might be a potential therapeutic agent by shaping microglial activation phenotypes during the course of neurodegenerative diseases such as PD. In this study, we demonstrate that TGF1 is able to block IFN-induced microglia activation by attenuating STAT1 phosphorylation and IFNR expression. Moreover, we identified a set of genes involved in microglial IFN signaling transduction that were significantly down-regulated upon TGF1 treatment, resulting in decreased sensitivity of microglia toward IFN stimuli. Interestingly, genes mediating negative regulation of IFN signaling, such as SOCS2 and SOCS6, were up-regulated after TGF1 treatment. Finally, we demonstrate that TGF1 is capable of protecting midbrain dopaminergic (mDA) neurons from IFN-driven neurotoxicity in mixed neuron-glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of TGF1 as a key immunoregulatory factor for microglia by silencing IFN-mediated microglia activation and, thereby, rescuing mDA neurons from IFN-induced neurotoxicity.Interferon (IFN) is a potent pro-inflammatory factor that triggers the activation of microglia and the subsequent release of neurotoxic factors. Transforming growth factor 1 (TGF1) is able to inhibit the IFN-mediated activation of microglia, which is characterized by the release of nitric oxide (NO) and tumor necrosis factor (TNF). By decreasing the expression of IFN-induced genes as well as the signaling receptor IFNR1, TGF1 reduces the responsiveness of microglia towards IFN. In mixed neuron-glia cultures, TGF1 protects midbrain dopaminergic (mDA) neurons from IFN-induced neurotoxicity.