A Unique Type of Highly-Activated Microglia Evoking Brain Inflammation via Mif/Cd74 Signaling Axis in Aged Mice
Chenghao Jin1, Yijie Shao1, Xiaotao Zhang1
11Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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.
Insights
Aging brains exhibit altered microglia, a type of immune cell. Researchers identified a unique highly-activated microglia (HAM) subgroup, driven by neuron signals, contributing to brain inflammation in aged mice.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Senescence-associated changes in microglia are emerging as critical factors in the aged brain.
- Chronic inflammation in aged microglia is observed, but underlying mechanisms require elucidation.
Purpose of the Study:
- To investigate the functional and molecular characteristics of microglia in the aged brain at the single-cell level.
- To identify specific microglial subgroups and their roles in age-related neuroinflammation.
Main Methods:
- Morphological detection and single-cell RNA sequencing of microglia from aged and young mice.
- Transcriptomic analysis to identify distinct microglial subgroups and their gene expression profiles.
Main Results:
- Aged mice displayed increased quantity and volume of microglia.
- Six distinct microglial subgroups were identified; three showed significant age-related variations.
- A novel highly-activated microglia (HAM) subgroup, expressing Lpl, Lgals3, Cst7, and Cd74, was identified exclusively in aged mice.
- HAM exhibited activated gene clusters related to cell survival, metabolism, and inflammatory responses.
- Neuron-derived Mif, via the Cd74 receptor on HAM, was found to drive microglial chemotaxis and subsequent inflammation.
Conclusions:
- A specific mechanism involving neuron-microglia communication (Mif-Cd74 axis) drives age-related brain inflammation.
- Highly-activated microglia (HAM) play a key role in the inflammatory milieu of the aged brain.
- Targeting the Mif-Cd74 pathway presents a potential therapeutic strategy for mitigating age-related neuroinflammation and promoting brain health.
