State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China;
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2023290118.
Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis-FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.
视网膜新生血管是导致人类严重视力丧失的主要原因，而小胶质细胞激活驱动血管生成的分子机制尚不清楚。通过单细胞 RNA 测序，我们鉴定出一个名为 sMG2 的小胶质细胞亚群，该亚群高度表达细胞坏死相关基因 Rip3 和 Mlkl。遗传和药理学功能丧失实验表明，缺氧诱导的小胶质细胞激活通过 RIP1/RIP3 介导的途径导致细胞坏死。小胶质细胞中 Rip3 基因的特异性缺失显著减少了视网膜新生血管形成。此外，缺氧通过 RIP3 介导的细胞坏死在小胶质细胞中诱导大量 FGF2 的爆发性释放。重要的是，阻断小胶质细胞坏死-FGF2 轴的信号成分在很大程度上抑制了视网膜血管生成，同时阻断 VEGF 的联合治疗产生了协同的抗血管生成作用。总之，我们的数据表明，靶向小胶质细胞坏死轴是治疗视网膜新生血管疾病的一种抗血管生成疗法。
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