Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

中文翻译：

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烟酸介导的巨噬细胞/小胶质细胞再生增强了老化中枢神经系统的髓鞘再生。

CNS 脱髓鞘后的髓鞘再生可恢复快速信号传播并保护轴突；然而，其效率随着年龄的增长而下降。少突胶质细胞祖细胞群的内在变化和老年受试者病变微环境中的外在因素都导致了这种下降。小胶质细胞和单核细胞衍生的巨噬细胞对于成功的髓鞘再生、释放生长因子和清除抑制性髓鞘碎片至关重要。几项研究表明巨噬细胞/小胶质细胞延迟募集到病变中是导致老年受试者髓鞘再生减少的关键因素。在这里，我们表明衰老小鼠小胶质细胞和人类小胶质细胞在培养物中清道夫受体 CD36 的表达降低是它们吞噬活性降低的基础。培养的小胶质细胞中 CD36 的过度表达可挽救髓鞘碎片吞噬作用的缺陷。通过筛选临床批准的刺激巨噬细胞/小胶质细胞的药物，我们发现烟酸（维生素 B3）上调 CD36 表达并增强培养物中小胶质细胞的髓鞘吞噬作用。这种髓磷脂吞噬作用的增加是通过烟酸受体（羟基羧酸受体 2）介导的。遗传命运图谱和多光子实时成像表明，用治疗相关剂量的烟酸对 9-12 个月大的脱髓鞘小鼠进行全身治疗，可促进外周来源的巨噬细胞和小胶质细胞清除病变中的髓鞘碎片。这伴随着少突胶质细胞祖细胞数量的增加和治疗小鼠髓鞘再生的改善。