Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection
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Published on: September 12, 2016
Alan Sariol1, Samantha Mackin2, Merri-Grace Allred1
1Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242.
Abstract:
Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus [MHV], strain JHMV), we show that depletion of microglia during the time of JHMV clearance resulted in impaired myelin repair and prolonged clinical disease without affecting the kinetics of virus clearance. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Furthermore, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial functions affected by depletion could not be compensated by infiltrating macrophages. Together, these results demonstrate that microglia play key roles in debris clearance and in the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.
Insights
Microglia are crucial for clearing myelin debris and initiating repair after coronavirus infection. Their depletion impairs myelin repair and prolongs disease, highlighting their essential early-stage role in central nervous system recovery.
Area of Science:
- Neuroimmunology
- Neurovirology
- Demyelinating Diseases
Background:
- Microglia's dual role in demyelination recovery is poorly understood.
- Understanding microglia's specific functions is critical for developing therapeutic strategies.
Purpose of the Study:
- To elucidate the precise role of microglia in myelin repair following viral-induced demyelination.
- To investigate the impact of microglia depletion on central nervous system recovery from neurotropic coronavirus infection.
Main Methods:
- Utilized colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in mice infected with mouse hepatitis virus (MHV).
- Analyzed myelin repair, clinical disease progression, viral clearance kinetics, and oligodendrocyte numbers.
- Performed gene expression analysis to identify molecular pathways involved in microglial function.
Main Results:
- Microglia depletion during viral clearance impaired myelin repair and prolonged disease, without affecting virus clearance.
- Large deposits of myelin debris were observed in treated mice, correlating with reduced oligodendrocyte numbers.
- Gene expression revealed altered pathways for debris clearance, lipid recycling, and oligodendrocyte support; macrophages could not compensate for microglia loss.
Conclusions:
- Microglia are essential for efficient myelin debris clearance and initiating remyelination after neurotropic coronavirus infection.
- Microglial functions are critical during early remyelination stages but not required for later repair processes.
- Infiltrating macrophages do not compensate for the loss of microglial functions in this model.
