A Unique Type of Highly-Activated Microglia Evoking Brain Inflammation via Mif/Cd74 Signaling Axis in Aged Mice.
A Unique Type of Highly-Activated Microglia Evoking Brain Inflammation via Mif/Cd74 Signaling Axis in Aged Mice.
复制标题
一种独特的高度激活的小胶质细胞通过 Mif/Cd74 信号轴在老年小鼠中诱发脑部炎症
DOI：
10.14336/ad.2021.0520
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发表时间：
2021-12
影响因子：
7.4
通讯作者：
Shi L
中科院分区：
文献类型：
--
作者：
Jin C;Shao Y;Zhang X;Xiang J;Zhang R;Sun Z;Mei S;Zhou J;Zhang J;Shi L
衰老相关的小胶质细胞改变直到最近才在老年人的大脑中被认识到。尽管我们之前的研究已经报道了老年小胶质细胞的慢性炎症，但其机制仍然知之甚少。在这里，我们在单细胞水平上对衰老的小胶质细胞进行了形态检测和转录分析。老龄小鼠脑内小胶质细胞数量多，体积大。通过单细胞RNA测序鉴定出6个具有独特功能的小胶质细胞亚群。在六个亚组中，有三个亚组的小胶质细胞在老年和年轻小鼠之间表现出显著的差异。仅在老年小鼠中观察到一种独特的高度激活的小胶质细胞(HAM)，具有几种标记的特异性表达，包括LPL、Lgals3、Cst7和CD74。在HAM中，与细胞存活、能量代谢和免疫炎症反应有关的功能基因簇显著激活。机制上，神经元释放的Mif通过HAM中的CD74受体作用，促进小胶质细胞的免疫趋化活性，从而在老年脑内引发免疫炎症反应。这些发现可能会揭示减少与年龄相关的脑部炎症以维持大脑健康的新目标。
Senescence-associated alterations of microglia have only recently been appreciated in the aged brain. Although our previous study has reported chronic inflammation in aged microglia, the mechanism remains poorly understood. Here, we performed morphological detection and transcriptomic analysis of aged microglia at the single cell level. Aged mice showed a large quantity and a large body volume of microglia in the brain. Six subgroups of microglia with unique function were identified by single cell RNA sequencing. Three out of six subgroups showed dramatic variations in microglia between aged and young mice. A unique type of highly-activated microglia (HAM) was observed in aged mice only, with specific expression of several markers, including Lpl, Lgals3, Cst7, and Cd74. Gene clusters with functional implications in cell survival, energy metabolism, and immuno-inflammatory responses were markedly activated in HAM. Mechanistically, neuron-released Mif, acting through Cd74 receptor in HAM, promoted the immunochemotactic activity of microglia, which then triggered immuno-inflammatory responses in aged brains. These findings may reveal new targets for reducing age-related brain inflammation to maintain brain health.