Single-cell microglial transcriptomics during demyelination defines a microglial state required for lytic carcass...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia are critical immune cells in the central nervous system, regulating responses to injury and disease.
• In white matter diseases, microglia can contribute to demyelination, but their precise role and response mechanisms remain unclear.

Purpose of the Study:

• To investigate microglial dynamics and subpopulations during cuprizone-induced demyelination.
• To elucidate the role of microglia in clearing dead oligodendrocytes.
• To understand the factors contributing to the distinct microglial state observed during demyelination.

Main Methods:

• Mice were fed cuprizone, a demyelinating agent, and genetically fate-mapped microglia dynamics were assessed.
• Single-cell RNA sequencing identified microglial subpopulations during demyelination.
• Microglial ablation and acridine orange staining were used to study oligodendrocyte clearance.
• Primary microglial cultures were treated to model cuprizone-induced demyelination.

Main Results:

• Cuprizone induced a significant microglial response by week 4.
• Single-cell RNA sequencing identified distinct cuprizone-associated microglia (CAM) clusters with signatures of cytokine regulation, ROS production, and phagocytosis.
• Microglia preferentially phagocytose lytic cell debris.
• In vitro, phagocytosis of lytic carcasses induced a CAM-like state in microglia.

Conclusions:

• Microglia exhibit diverse roles in demyelination, with a transcriptomic state similar to other neurodegenerative conditions.
• Phagocytosis of cellular debris is a likely driver of this common microglial state in neurodegeneration.