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.

小胶质细胞在脱髓鞘恢复过程中被认为既具有致病性又具有保护性，但其确切作用仍不明确。在这里，我们使用集落刺激因子 1 受体 (CSF1R) 抑制剂 PLX5622 和感染神经性冠状病毒（小鼠肝炎病毒 [MHV]，JHMV 株）的小鼠，发现在 JHMV 清除期间小胶质细胞的消耗导致髓磷脂修复受损和临床疾病延长，而不影响病毒清除动力学。仅在髓鞘再生的早期阶段需要小胶质细胞。值得注意的是，在 PLX5622 治疗小鼠而非对照小鼠的脊髓中检测到大量细胞外囊泡髓磷脂和细胞碎片沉积，这与药物治疗小鼠脱髓鞘病变中少突胶质细胞数量减少相关。此外，基因表达分析表明，参与髓鞘碎片清除、脂质和胆固醇循环以及促进少突胶质细胞功能的基因存在差异表达。结果还表明，受耗竭影响的小胶质细胞功能无法通过浸润巨噬细胞来补偿。总之，这些结果表明，小胶质细胞在碎片清除和感染嗜神经冠状病毒后髓鞘再生的启动中发挥着关键作用，但在髓鞘再生的后期阶段并不是必需的。