Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065.
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13272-13277. doi: 10.1073/pnas.1710493114. Epub 2017 Nov 22.
Microglia (MG), a heterogeneous population of phagocytic cells, play important roles in central nervous system (CNS) homeostasis and neural plasticity. Under steady-state conditions, MG maintain homeostasis by producing antiinflammatory cytokines and neurotrophic factors, support myelin production, and remove synapses and cellular debris, as well as participating in "cross-correction," a process that supplies neurons with key factors for executing autophagy-lysosomal function. As sentinels for the immune system, MG also detect "danger" signals (pathogenic or traumatic insult), become activated, produce proinflammatory cytokines, and recruit monocytes and dendritic cells to the site of damage through a breached blood-brain barrier or via brain lymphatics. Failure to effectively resolve MG activation can be problematic and can lead to chronic inflammation, a condition proposed to underlie CNS pathophysiology in heritable brain disorders and age-related neurodegenerative and cognitive decline. Here, we show that APOBEC1-mediated RNA editing occurs within MG and is key to maintaining their resting status. Like bone marrow-derived macrophages, RNA editing in MG leads to overall changes in the abundance of edited proteins that coordinate the function of multiple cellular pathways. Conversely, mice lacking the APOBEC1 editing function in MG display evidence of dysregulation, with progressive age-related signs of neurodegeneration, characterized by clustering of activated MG, aberrant myelination, increased inflammation, and lysosomal anomalies that culminate in behavioral and motor deficiencies. Collectively, our study identifies posttranscriptional modification by RNA editing as a critical regulatory mechanism of vital cellular functions that maintain overall brain health.
小胶质细胞（MG）是一种异质性的吞噬细胞群体，在中枢神经系统（CNS）稳态和神经可塑性中发挥重要作用。在稳态条件下，MG 通过产生抗炎细胞因子和神经营养因子、支持髓鞘生成、清除突触和细胞碎片，以及参与“交叉校正”（一种为神经元提供执行自噬溶酶体功能所需关键因子的过程）来维持稳态。作为免疫系统的哨兵，MG 还可以检测到“危险”信号（病原体或创伤性损伤），被激活后产生促炎细胞因子，并通过血脑屏障或脑淋巴系统招募单核细胞和树突状细胞到损伤部位。MG 激活未能有效解决可能会出现问题，并导致慢性炎症，这种情况被认为是遗传性脑疾病和与年龄相关的神经退行性和认知能力下降的 CNS 病理生理学的基础。在这里，我们表明 APOBEC1 介导的 RNA 编辑发生在 MG 内，是维持其静息状态的关键。与骨髓来源的巨噬细胞一样，MG 中的 RNA 编辑导致编辑蛋白丰度的整体变化，协调多个细胞途径的功能。相反，缺乏 MG 中 APOBEC1 编辑功能的小鼠显示出失调的证据，随着年龄的增长出现进行性神经退行性病变的迹象，其特征是激活的 MG 聚集、异常髓鞘形成、炎症增加和溶酶体异常，最终导致行为和运动缺陷。总的来说，我们的研究确定了 RNA 编辑的转录后修饰作为维持大脑整体健康的重要细胞功能的关键调节机制。
