Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Institute of Traditional Chinese Medicine and Stem Cell Research, College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
Cell Death Dis. 2024 Aug 26;15(8):623. doi: 10.1038/s41419-024-07002-z.
Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of degeneration. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was established in C57BL/6 J (WT) and Trem2 knockout (Trem2) mice. We discovered that MNU treatment led to the concurrent processes of photoreceptor apoptosis and microglia infiltration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration. Following MNU treatment, Trem2 mice showed exacerbated photoreceptor cell death, decreased microglia migration and phagocytosis, reduced microglial PPARγ activation and CD36 expression. Pharmaceutical activation of PPARγ promoted microglial migration, ameliorated photoreceptor degeneration and restored CD36 expression in MNU-treated Trem2 mice. Inhibition of CD36 activity worsened photoreceptor degeneration in MNU-treated WT mice. Our findings suggested that the protective effect of microglia during retinal degeneration was dependent on Trem2 expression and carried out via the activation of PPARγ and the consequent upregulation of CD36 expression. Our study linked TREM2 signaling with PPARγ activation, and provided a potential therapeutic target for the management of retinal degeneration.
视网膜变性是一组具有进行性视力丧失的破坏性疾病，常导致失明。对视网膜小胶质细胞的研究为阻止变性进展提供了巨大的治疗潜力。本研究探讨了 TREM2 介导的激活小胶质细胞在视网膜变性过程中的保护功能的机制。在 C57BL/6J（WT）和 Trem2 敲除（Trem2）小鼠中建立了 N-甲基-N-亚硝基脲（MNU）诱导的视网膜变性模型。我们发现 MNU 处理导致光感受器细胞凋亡和小胶质细胞浸润的同时发生。在光感受器变性过程中观察到疾病相关小胶质细胞特征基因的显著上调。在 MNU 处理后，Trem2 小鼠表现出光感受器细胞死亡加剧、小胶质细胞迁移和吞噬作用减少、小胶质细胞 PPARγ 激活和 CD36 表达减少。PPARγ 的药物激活促进了小胶质细胞的迁移，改善了 MNU 处理的 Trem2 小鼠中的光感受器变性，并恢复了 CD36 的表达。在 MNU 处理的 WT 小鼠中抑制 CD36 活性会加重光感受器变性。我们的研究结果表明，小胶质细胞在视网膜变性过程中的保护作用依赖于 Trem2 表达，并通过激活 PPARγ 和随后上调 CD36 表达来实现。我们的研究将 TREM2 信号与 PPARγ 激活联系起来，为管理视网膜变性提供了一个潜在的治疗靶点。
