TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
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DOI：
10.1007/s00401-020-02193-z
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发表时间：
2020-08-09
影响因子：
12.7
通讯作者：
Piccio, Laura
中科院分区：
文献类型：
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作者：
Cignarella, Francesca;Filipello, Fabia;Piccio, Laura
多发性硬化症（MS）是一种由自身免疫机制引发的中枢神经系统（CNS）炎症、脱髓鞘和神经退行性疾病。小胶质细胞对于清除脱髓鞘区域的髓鞘碎片至关重要，这是髓鞘再生的关键步骤。 TREM2 由小胶质细胞表达，促进小胶质细胞存活、增殖和吞噬活性。在此，我们证明 TREM2 在 MS 受试者中枢神经系统活动性脱髓鞘病变中的髓磷脂吞噬细胞上高表达。在基因表达研究中，来自 TREM2 遗传缺陷受试者的巨噬细胞显示出吞噬途径的缺陷。在中枢神经系统脱髓鞘的铜宗模型中，使用新型 TREM2 激动性抗体进行治疗可促进髓鞘碎片的清除。效果包括增强髓磷脂的吸收和降解，导致小胶质细胞加速髓磷脂碎片的清除。最重要的是，小胶质细胞上抗体依赖性 TREM2 激活增加了脱髓鞘区域少突胶质细胞前体的密度，以及成熟少突胶质细胞的形成，从而增强了髓鞘再生和轴突完整性。这些结果是相关的，因为他们提出小胶质细胞上的 TREM2 作为促进髓鞘再生的潜在新靶点。
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.