Abstract
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.
Highlights
Microglia are the primary resident immune cells of the central nervous system (CNS) and constitute 5–12% of brain cells [1]
The present study provides single-cell transcriptional profiling of a unique type of highly-activated microglia from the brain of aged mice under homeostatic conditions
Major findings of our study included that (i) a unique type of microglia (HAM) identified by Lpl and Lgals3, were observed to reprogram their transcriptome to evoke inflammation in aged mice; (ii) no brain regional variation was detected in highly-activated microglia (HAM) in whole brain or in the subventricular zone (SVZ); (iii) the migration inhibitory factor (Mif)/Cd74 signaling axis triggers release of chemokines from HAM to recruit infiltration of peripheral immune cells into the aged brain
Summary
Microglia are the primary resident immune cells of the central nervous system (CNS) and constitute 5–12% of brain cells [1]. Using single cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF), only a small group of microglia was identified to be highly activated during aging [12, 13]. A recent study revealed that T cell infiltration of aged mouse brains led to decreased activation of neural stem cells [14] It remains to be determined whether recruitment of infiltrated T cells is related to aged microglia. Neuronreleased macrophage migration inhibitory factor (Mif) acts through the Cd74 receptor in HAM to promote immunochemotactic activity of microglia, which triggers immuno-inflammatory responses in the aged brain. These findings may create a new therapeutic avenue for antiaging and for preventing age-related neurodegenerative disorders
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