Pfeifer Charles W, Santeford Andrea, Apte Rajendra S
John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Neurosciences Graduate Program, Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Glia. 2025 Jul 11. doi: 10.1002/glia.70061.
Circadian rhythms govern various physiological processes, including innate and adaptive immune responses. Microglia, the sentinels of the central nervous system (CNS), mediate synaptic remodeling and local immune responses that contribute to tissue homeostasis. Recent studies have uncovered that microglial surveillance behavior and cytokine production exhibit rhythmicity. Furthermore, disruption of clock gene expression in microglia impairs phagocytic capacity, metabolism, and inflammatory responses, suggesting that their dynamic functions are regulated in part by circadian rhythms. Given the growing recognition of circadian dysregulation in disease pathophysiology, elucidating molecular mechanisms of microglial chronobiology may reveal novel therapeutic strategies to resynchronize circadian rhythms with components of the immune system. Homeostatic rhythms and the implications of their disruption have yet to be explored in microglia that reside within the neurosensory retina, a tissue in the back of the eye that initiates visual transduction and relays photic information to the brain. In this study, we demonstrate that retinal microglia express rhythms in clock gene expression, morphology, and inflammatory markers that rely on the clock gene Bmal1. We also find that loss of Bmal1 in microglia is associated with a decline in retinal health and behavioral dysfunction in the mouse. Lastly, we demonstrate that Bmal1 deficiency also induces a senescent, disease-associated phenotype in microglia and transcriptomic reprogramming in the retinal parenchyma. These findings suggest that diurnal clock rhythms regulate microglia physiology within the retinal niche and contribute to homeostatic maintenance of the local tissue environment.
昼夜节律控制着各种生理过程，包括先天性和适应性免疫反应。小胶质细胞作为中枢神经系统（CNS）的哨兵，介导突触重塑和局部免疫反应，有助于维持组织稳态。最近的研究发现，小胶质细胞的监测行为和细胞因子产生具有节律性。此外，小胶质细胞中生物钟基因表达的破坏会损害吞噬能力、新陈代谢和炎症反应，这表明它们的动态功能部分受昼夜节律调节。鉴于人们越来越认识到昼夜节律失调在疾病病理生理学中的作用，阐明小胶质细胞生物钟生物学的分子机制可能会揭示新的治疗策略，使昼夜节律与免疫系统的组成部分重新同步。位于神经感觉视网膜内的小胶质细胞中，稳态节律及其破坏的影响尚未得到探索，神经感觉视网膜是眼睛后部的一个组织，它启动视觉转导并将光信息传递给大脑。在本研究中，我们证明视网膜小胶质细胞在生物钟基因表达、形态和炎症标志物方面表现出节律性，这些节律依赖于生物钟基因Bmal1。我们还发现，小胶质细胞中Bmal1的缺失与小鼠视网膜健康下降和行为功能障碍有关。最后，我们证明Bmal1缺乏还会在小胶质细胞中诱导衰老的、与疾病相关的表型，并在视网膜实质中引起转录组重编程。这些发现表明，昼夜生物钟节律调节视网膜微环境中的小胶质细胞生理学，并有助于维持局部组织环境的稳态。
