Activated microglia drive demyelination via CSF1R signaling

Area of Science:

• Neuroimmunology
• Neuroinflammation
• Demyelinating Diseases

Background:

• Microgliosis is a hallmark of neurological disorders, including multiple sclerosis (MS).
• The exact function of microglia and peripheral macrophages in demyelination is unclear.
• Distinguishing between microglia and macrophages is challenging with current markers.

Purpose of the Study:

• To elucidate the role of microglia in demyelination using a genetic fate mapping strategy.
• To investigate the involvement of Colony-stimulating factor 1 (CSF1) in microglial responses and demyelination.
• To determine whether microglia or astrocytes are the primary drivers of demyelination in the cuprizone model.

Main Methods:

• Genetic fate mapping in the cuprizone (CUP) model.
• Depletion of microglia using the CSF1R inhibitor PLX3397.
• Electron microscopy (EM) and serial block face imaging.
• Direct injection of CSF1 into the CNS.
• Analysis of mice with impaired microglial-astrocyte interactions.

Main Results:

• Microglia are the primary responders and effectors of demyelination in the CUP model.
• CSF1R inhibition abrogates demyelination, oligodendrocyte loss, and astrocytosis.
• Myelin sheaths remain intact without microglia; phagocytosis occurs upon repopulation.
• CSF1 injection induces microgliosis and demyelination, indicating CSF1 signaling drives demyelination.
• Demyelination occurs normally in mice lacking toxic astrocyte phenotypes, implicating microglia as primary drivers.

Conclusions:

• Activated microglia are necessary for and directly drive demyelination.
• CSF1 signaling plays a critical role in mediating microglial-driven demyelination.
• Microglia, not astrocytes, are the primary drivers of cuprizone-induced demyelination.