Liu Yang, Hao Wenlin, Dawson Alik, Liu Shirong, Fassbender Klaus
Department of Neurology, University of the Saarland, D-66421 Homburg/Saar, Germany.
J Biol Chem. 2009 Feb 6;284(6):3691-9. doi: 10.1074/jbc.M804446200. Epub 2008 Dec 17.
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-alpha secretion at a post-transcriptional level and involved ROS-sensitive TNF-alpha-converting enzymes, e.g. ADAM10 and -17, which shed TNF-alpha from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.
肌萎缩侧索硬化症（ALS）是一种进行性运动神经元疾病，已知在该疾病中，过表达与ALS相关的超氧化物歧化酶1突变体（mSOD1）的活化小胶质细胞会导致神经元死亡。然而，目前尚不清楚mSOD1的表达如何影响小胶质细胞的活化并随后损害神经元。在本研究中，我们创建了过表达mSOD1的BV-2小胶质细胞系。在受到Toll样受体2（TLR2）而非Toll样受体4（TLR4）刺激后，我们观察到，与野生型SOD1或模拟对照相比，人SOD1 G93A、L8Q或G10V突变体的过表达显著增强了小胶质细胞分泌神经毒性细胞因子肿瘤坏死因子-α（TNF-α），这依赖于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶介导的活性氧（ROS）生成增加。在进一步的实验中，我们证明mSOD1的表达在转录后水平调节TNF-α的分泌，并且涉及对ROS敏感的TNF-α转换酶，例如ADAM10和ADAM17，它们从膜锚定前体中裂解TNF-α。结合最近的一份报告，即由于其基因突变，SOD1作为NADPH氧化酶依赖性ROS产生中的自调节氧化还原传感器的功能丧失，我们得出结论，ALS中mSOD1的表达通过TLR2促进小胶质细胞的神经毒性炎症反应，这是由不受控制的ROS生成介导的。mSOD1、固有免疫和NADPH氧化酶之间的联系为ALS治疗提供了新的机会。
