TREM2依赖性小胶质细胞功能对于髓鞘再生及其神经保护至关重要  

TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection

作　　者：YuanyuanWang Roxanne V Kyauk Yun-An A Shen Luke Xie Mike Reichelt Han Lin Zhiyu Jiang Hai Ngu Kimberle Shen Jacob J Greene Morgan Sheng Tracy J Yuen 杜一星(编译) 

机构地区：[1]Department of Neuroscience,Genentech Inc.,South San Francisco,California,USA [2]Department of Biomedical Imaging,Genentech Inc.,South San Francisco,California,USA [3]Department of Pathology,Genentech Inc.,South San Francisco,California,USA [4]Stanley Center for Psychiatric Research,Broad Institute of MIT and Harvard,Cambridge,Massachusetts,USA. [5]不详

出　　处：《神经损伤与功能重建》2023年第7期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：多发性硬化症(MS)的残疾在一定程度上是由髓鞘再生失败和进行性神经变性引起的。小胶质细胞和髓系细胞触发受体2(TREM2)(一种在小胶质细胞中高度表达的因子)已被证明在髓鞘再生中发挥重要作用。本研究使用大脑局灶性脱髓鞘模型,证明脱髓鞘在TREM2敲除小鼠中持续存在;脱髓鞘在注射溶血卵磷脂后持续超过6周,并导致严重的神经变性。我们还发现TREM2敲除小鼠在脱髓鞘后表现出神经胶质反应的改变。TREM2敲除小胶质细胞表现出迁移和吞噬髓磷脂碎片的缺陷。此外,来自携带人类疾病中普遍存在的TREM2突变的受试者的人类单核细胞衍生的巨噬细胞也显示出髓磷脂碎片吞噬作用的缺陷。综上所述,我们强调了TREM2信号在髓鞘再生和神经保护中的核心作用。这些发现揭示了慢性脱髓鞘如何导致轴突损伤,并有助于确定多发性硬化症的新型神经保护治疗靶点。Disability in multiple sclerosis(MS)is driven in part by the failure of remyelination and progressive neu-rodegeneration.Microglia,and specifically triggering receptor expressed on myeloid cells 2(TREM2),a factor high-ly expressed in microglia,have been shown to play an important role in remyelination.Here,using a focal demyelin-ation model in the brain,we demonstrate that demyelination is persistent in TREM2 knockout mice,lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration.We also find that TREM2 knockout mice exhibit an altered glial response following demyelination.TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris.In addition,human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis.To-gether,we highlight the central role of TREM2 signaling in remyelination and neuroprotection.These findings pro-vide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuropro-tective therapeutic targets for MS.

关 键 词：髓系细胞触发受体2 轴突变性 脱髓鞘 小胶质细胞 多发性硬化症 少突胶质细胞 髓鞘再生 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]