Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
Immunity. 2018 Mar 20;48(3):514-529.e6. doi: 10.1016/j.immuni.2018.02.016. Epub 2018 Mar 13.
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.
小胶质细胞作为组织巨噬细胞，有助于中枢神经系统 (CNS) 的防御和维持内环境稳定。目前对于控制小胶质细胞功能的表观遗传信号知之甚少。我们在小胶质细胞中使用组成性和诱导性突变来删除两种 I 类组蛋白去乙酰化酶，Hdac1 和 Hdac2。Hdac1 和 Hdac2 的产前缺失会损害小胶质细胞的发育。从机制上讲，在缺乏 Hdac1 和 Hdac2 的情况下，促凋亡和细胞周期基因的启动子被过度乙酰化，导致细胞凋亡增加和存活减少。相比之下，Hdac1 和 Hdac2 在稳态期间对于成年小胶质细胞的存活并不必需。在阿尔茨海默病的小鼠模型中，小胶质细胞中 Hdac1 和 Hdac2 的缺失（而非神经外胚层细胞）导致淀粉样蛋白负荷减少，并通过增强小胶质细胞的淀粉样蛋白吞噬作用改善认知障碍。总之，我们报告了表观遗传因素在小胶质细胞发育、稳态和疾病中的作用，这些因素可能具有治疗潜力。
