Musculoskeletal Diseases Area, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland.
Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland.
J Neuroinflammation. 2023 Feb 8;20(1):29. doi: 10.1186/s12974-022-02671-z.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells and macrophages. Heterozygous loss-of-function mutations in TREM2, including mutations enhancing shedding form the cell surface, have been associated with myelin/neuronal loss and neuroinflammation in neurodegenerative diseases, such as Alzheimer`s disease and Frontotemporal Dementia. Using the cuprizone model, we investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes in cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knockout (TREM2-KO) and wild-type (WT) mice. The TREM2-sol mouse is a new model with selective elimination of plasma membrane TREM2 and a reduced expression of soluble TREM2. In the acute cuprizone model demyelination and remyelination events were reflected by a T2-weighted signal intensity change in magnetic resonance imaging (MRI), most prominently in the external capsule (EC). In contrast to WT and TREM2-IPD, TREM2-sol and TREM2-KO showed an additional increase in MRI signal during the recovery phase. Histological analyses of TREM2-IPD animals revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1 and displayed enhanced cytokine/chemokine levels in the brain. TREM2-sol and, to a much lesser extent, TREM2-KO, however, despite presenting reduced levels of some cytokines/chemokines, showed persistent microgliosis and astrocytosis during recovery, with both homeostatic (TMEM119) as well as activated (LAMP-1) microglia markers increased. This was accompanied, specifically in the EC, by no myelin recovery, with appearance of myelin debris and axonal pathology, while oligodendrocytes recovered. In the chronic model consisting of 12-week cuprizone administration followed by 3-week recovery TREM2-IPD displayed sustained microgliosis and enhanced remyelination in the recovery phase. Taken together, our data suggest that sustained microglia activation led to increased remyelination, whereas microglia without plasma membrane TREM2 and only soluble TREM2 had reduced phagocytic activity despite efficient lysosomal function, as observed in bone marrow-derived macrophages, leading to a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology following cuprizone intoxication.
触发受体表达在髓样细胞 2（TREM2）是一种细胞表面免疫受体表达在小胶质细胞，破骨细胞，树突状细胞和巨噬细胞。异源失活突变 TREM2，包括突变增强脱落形式的细胞表面，已与髓鞘/神经元损失和神经炎症在神经退行性疾病，如阿尔茨海默病和额颞叶痴呆。使用 cuprizone 模型，我们研究了可溶性和切割减少 TREM2 对中枢髓鞘形成过程的参与切割减少（TREM2-IPD），可溶性仅（TREM2-sol），敲除（TREM2-KO）和野生型（WT）小鼠。TREM2-sol 是一种新的模型，具有选择性消除质膜 TREM2 和可溶性 TREM2 的表达减少。在急性 cuprizone 模型脱髓鞘和髓鞘再生事件反映了 T2 加权磁共振成像（MRI）信号强度的变化，在外囊（EC）中最为明显。与 WT 和 TREM2-IPD 相比，TREM2-sol 和 TREM2-KO 在恢复阶段显示出 MRI 信号的额外增加。TREM2-IPD 动物的组织学分析显示神经炎症以及溶酶体标记物 LAMP-1 无恢复，并显示大脑中细胞因子/趋化因子水平升高。然而，TREM2-sol 和 TREM2-KO 尽管某些细胞因子/趋化因子水平降低，但在恢复期间仍表现出持续的小胶质细胞增生和星形胶质细胞增生，并且两种稳态（TMEM119）和激活（LAMP-1）小胶质细胞标记物均增加。这伴随着特定的髓鞘再生，在外囊（EC）中，髓鞘碎片和轴突病理学的出现，而少突胶质细胞恢复。在由 12 周 cuprizone 给药和随后 3 周恢复组成的慢性模型中，TREM2-IPD 在恢复阶段显示持续的小胶质细胞激活和增强的髓鞘再生。总之，我们的数据表明，持续的小胶质细胞激活导致髓鞘再生增加，而没有质膜 TREM2 且仅具有可溶性 TREM2 的小胶质细胞尽管具有有效的溶酶体功能，但吞噬活性降低，如骨髓来源的巨噬细胞中观察到的，导致功能失调表型，髓鞘碎片清除不当，缺乏髓鞘再生和轴突病理学在 cuprizone 中毒后。
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