Department of Neurology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road West, Guangzhou, Guangdong, 510630, China.
Department of Neurology, The First People's Hospital of Huaihua, Affiliated to University of South China, No. 144, Jinxi Road South, Huaihua, 418000, China.
J Mol Neurosci. 2017 Oct;63(2):159-164. doi: 10.1007/s12031-017-0966-1. Epub 2017 Aug 31.
It is well known that extracellular deposition of amyloid-β (Aβ) peptide and microglia-mediated neuroinflammation are major hallmarks of Alzheimer's disease (AD). Interferon regulatory factor-8 (IRF-8), an important transcription factor of the IRF family, is highly restricted in microglia in brains. The expression pattern and function of IRF-8 in AD need to be elucidated in order to provide novel therapies for the treatment of AD. In this study, our results indicated that expression of IRF-8 is significantly elevated in the brains and microglia of AD transgenic model Tg2576 mice. Notably, in vitro cell culture and reporter luciferase assay show that Aβ treatment promotes expression of IRF-8 at the transcriptional level. Silencing of IRF-8 in microglia abolished Aβ-induced elevation in typical activated microglia-related genes, including the microglial innate response receptor toll-like receptor 2 (TLR2), the chemotaxis gene purinergic receptor PYR, and the proinflammatory cytokine IL-1β. However, overexpression of IRF-8 exacerbated the elevated expression of these proteins. Finally, the JAK2/STAT-1 pathway was found to mediate Aβ-induced elevation of IRF-8. Overall, this is the first time to report that IRF-8 is involved in microglial activation and neuroinflammation in AD.
众所周知，细胞外淀粉样β（Aβ）肽的沉积和小胶质细胞介导的神经炎症是阿尔茨海默病（AD）的主要标志。干扰素调节因子-8（IRF-8）是 IRF 家族的一个重要转录因子，在大脑中的小胶质细胞中高度受限。为了为 AD 的治疗提供新的疗法，需要阐明 AD 中 IRF-8 的表达模式和功能。在这项研究中，我们的结果表明，IRF-8 的表达在 AD 转基因模型 Tg2576 小鼠的大脑和小胶质细胞中显着升高。值得注意的是，体外细胞培养和报告基因荧光素酶测定表明，Aβ 处理可促进 IRF-8 在转录水平的表达。在小胶质细胞中沉默 IRF-8 可消除 Aβ 诱导的典型激活小胶质细胞相关基因的升高，包括小胶质细胞固有反应受体 Toll 样受体 2（TLR2）、趋化基因嘌呤能受体 PYR 和促炎细胞因子 IL-1β。然而，IRF-8 的过表达加剧了这些蛋白的升高表达。最后，发现 JAK2/STAT-1 途径介导 Aβ 诱导的 IRF-8 升高。总的来说，这是首次报道 IRF-8 参与 AD 中的小胶质细胞激活和神经炎症。
