Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104.
Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5102-5107. doi: 10.1073/pnas.1812405116. Epub 2019 Feb 21.
Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.
昼夜节律紊乱是许多神经退行性疾病的共同特征，其中大多数与神经炎症有关。昼夜节律紊乱与外周炎症有关，但核心时钟在神经炎症中的作用仍知之甚少。在这里，我们证明了核受体和昼夜节律钟成分 Rev-erbα 是小胶质细胞激活和神经炎症的介质。我们观察到海马体中小胶质细胞免疫反应的昼夜节律波动，而 Rev-erbα 小鼠则存在这种波动。Rev-erbα 缺失导致海马体中小胶质细胞自发激活，并增加促炎转录本的表达以及继发的星形胶质细胞增生。Rev-erbα 小鼠海马体的转录组分析显示出主要的炎症表型，并提示 NF-κB 信号失调。原代 Rev-erbα 小胶质细胞表现出促炎表型，并增加基础 NF-κB 激活。染色质免疫沉淀显示 Rev-erbα 与原代小胶质细胞中几个 NF-κB 相关基因的启动子区域发生物理相互作用。原代星形胶质细胞中 Rev-erbα 的缺失对基础激活没有影响，但增强了对脂多糖 (LPS) 的炎症反应。在体内，Rev-erbα 小鼠对外周 LPS 注射表现出增强的海马体神经炎症反应，而用小分子激动剂 SR9009 激活 Rev-erbs 可抑制 LPS 诱导的海马体神经炎症。Rev-erbα 的缺失影响神经元健康，因为来自 Rev-erbα 缺失的原代神经胶质培养物的条件培养基加剧了培养神经元中的氧化损伤。Rev-erbα 小鼠还表现出明显改变的皮质静息状态功能连接，类似于在神经退行性模型中观察到的情况。我们的研究结果揭示了 Rev-erbα 作为昼夜节律钟和神经炎症之间的药理学联系。
