Zhou Xiaolai, Zöller Tanja, Krieglstein Kerstin, Spittau Björn
Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Freiburg, Germany.
J Neurochem. 2015 Jul;134(1):125-34. doi: 10.1111/jnc.13111. Epub 2015 Apr 23.
Microglia-mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinson's disease (PD), and a growing body of evidence indicates that onset and progression of PD correlates with the extent of neuroinflammatory responses involving Interferon γ (IFNγ). Transforming growth factor β1 (TGFβ1) 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 TGFβ1 is able to block IFNγ-induced microglia activation by attenuating STAT1 phosphorylation and IFNγRα expression. Moreover, we identified a set of genes involved in microglial IFNγ signaling transduction that were significantly down-regulated upon TGFβ1 treatment, resulting in decreased sensitivity of microglia toward IFNγ stimuli. Interestingly, genes mediating negative regulation of IFNγ signaling, such as SOCS2 and SOCS6, were up-regulated after TGFβ1 treatment. Finally, we demonstrate that TGFβ1 is capable of protecting midbrain dopaminergic (mDA) neurons from IFNγ-driven neurotoxicity in mixed neuron-glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of TGFβ1 as a key immunoregulatory factor for microglia by silencing IFNγ-mediated microglia activation and, thereby, rescuing mDA neurons from IFNγ-induced neurotoxicity. Interferon γ (IFNγ) is a potent pro-inflammatory factor that triggers the activation of microglia and the subsequent release of neurotoxic factors. Transforming growth factor β1 (TGFβ1) is able to inhibit the IFNγ-mediated activation of microglia, which is characterized by the release of nitric oxide (NO) and tumor necrosis factor α (TNFα). By decreasing the expression of IFNγ-induced genes as well as the signaling receptor IFNγR1, TGFβ1 reduces the responsiveness of microglia towards IFNγ. In mixed neuron-glia cultures, TGFβ1 protects midbrain dopaminergic (mDA) neurons from IFNγ-induced neurotoxicity.
小胶质细胞介导的神经炎症已被报道为家族性和散发性帕金森病（PD）的一个共同特征，越来越多的证据表明，PD的发病和进展与涉及干扰素γ（IFNγ）的神经炎症反应程度相关。转化生长因子β1（TGFβ1）已被证明是调节小胶质细胞激活状态和功能的主要参与者，因此，在PD等神经退行性疾病过程中，通过塑造小胶质细胞激活表型，它可能是一种潜在的治疗剂。在本研究中，我们证明TGFβ1能够通过减弱STAT1磷酸化和IFNγRα表达来阻断IFNγ诱导的小胶质细胞激活。此外，我们鉴定了一组参与小胶质细胞IFNγ信号转导的基因，在TGFβ1处理后它们显著下调，导致小胶质细胞对IFNγ刺激的敏感性降低。有趣的是，介导IFNγ信号负调控的基因，如SOCS2和SOCS6，在TGFβ1处理后上调。最后，我们证明TGFβ1能够在源自胚胎第14天（E14）中脑组织的混合神经元-胶质细胞培养物中保护中脑多巴胺能（mDA）神经元免受IFNγ驱动的神经毒性。总之，这些数据强调了TGFβ1作为小胶质细胞关键免疫调节因子的重要性，它通过沉默IFNγ介导的小胶质细胞激活，从而使mDA神经元免受IFNγ诱导的神经毒性。干扰素γ（IFNγ）是一种强大的促炎因子，可触发小胶质细胞的激活及随后神经毒性因子的释放。转化生长因子β1（TGFβ1）能够抑制IFNγ介导的小胶质细胞激活，其特征是一氧化氮（NO）和肿瘤坏死因子α（TNFα）的释放。通过降低IFNγ诱导基因以及信号受体IFNγR1的表达，TGFβ1降低了小胶质细胞对IFNγ的反应性。在混合神经元-胶质细胞培养物中，TGFβ1保护中脑多巴胺能（mDA）神经元免受IFNγ诱导的神经毒性。
