He Jincan, Zhou Wenchuan, Li Jing
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai, 200092, China.
Cell Commun Signal. 2025 Jun 4;23(1):267. doi: 10.1186/s12964-025-02261-5.
Various functions of activated microglia play crucial roles in the progression of retinitis pigmentosa (RP). This study aims to investigate the mechanisms underlying microglial migratory responses and phagocytic activity and their effects on photoreceptor degeneration.
Trem2-deficient rd10 mice (Trem2:rd10) were used in this study. N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was established in microglia-specific Trem2 overexpression mice (Tmem119:Rosa26). IFN-α/β receptor I (IFNAR1) neutralizing antibody was used to achieve type I interferon (IFN-I) signaling blockade. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), immunofluorescent staining and western blot analysis were used to assess microglial responses and photoreceptor cell apoptosis. Microglia were purified with CD11b MicroBeads. Transcriptomic profiles of the whole retina were generated and analyzed.
Progressive photoreceptor cell death and sustained microglial migratory responses were observed throughout the degeneration process in rd10 mice and MNU model. Trem2-deficient microglia displayed impaired migratory responses and subsequent phagocytosis, affecting photoreceptor cell survival at different stages of rd10 mice. Conversely, microglia-specific Trem2 overexpression mice showed enhanced microglial migration following MNU treatment. Furthermore, we found IFN-I signaling pathway was associated with microglial migration, which was regulated by TREM2 expression. Exogenous IFN-I blockade weakened microglial migration and reversed the effects of photoreceptor cell death caused by Trem2 overexpression.
Our findings demonstrated the divergent roles of Trem2-mediated microglial migratory responses and phagocytic activity at different stages of RP-featured retinal degeneration models. We identified the link between Trem2 and IFN-I signaling in microglia and provided a potential microglia-associated target for RP therapy.
活化小胶质细胞的多种功能在色素性视网膜炎（RP）的进展中起关键作用。本研究旨在探讨小胶质细胞迁移反应和吞噬活性的潜在机制及其对光感受器变性的影响。
本研究使用Trem2基因敲除的rd10小鼠（Trem2:rd10）。在小胶质细胞特异性Trem2过表达小鼠（Tmem119:Rosa26）中建立N-甲基-N-亚硝基脲（MNU）诱导的视网膜变性。使用IFN-α/β受体I（IFNAR1）中和抗体实现I型干扰素（IFN-I）信号通路阻断。采用末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）、免疫荧光染色和蛋白质印迹分析来评估小胶质细胞反应和光感受器细胞凋亡。用CD11b微珠纯化小胶质细胞。生成并分析整个视网膜的转录组图谱。
在rd10小鼠和MNU模型的整个变性过程中，观察到光感受器细胞进行性死亡和小胶质细胞持续迁移反应。Trem2基因敲除的小胶质细胞表现出迁移反应受损以及随后的吞噬作用受损，影响rd10小鼠不同阶段的光感受器细胞存活。相反，小胶质细胞特异性Trem2过表达小鼠在MNU处理后显示小胶质细胞迁移增强。此外，我们发现IFN-I信号通路与小胶质细胞迁移相关，其受TREM2表达调节。外源性IFN-I阻断减弱了小胶质细胞迁移，并逆转了Trem2过表达导致的光感受器细胞死亡效应。
我们的研究结果表明，在以RP为特征的视网膜变性模型的不同阶段，Trem2介导的小胶质细胞迁移反应和吞噬活性具有不同作用。我们确定了Trem2与小胶质细胞中IFN-I信号通路之间的联系，并为RP治疗提供了一个潜在的小胶质细胞相关靶点。
