A specific RIP3(+) subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism.
A specific RIP3(+) subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism.
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小胶质细胞的特定 RIP3( ) 亚群通过缺氧触发的坏死性凋亡机制促进视网膜病变。
DOI：
10.1073/pnas.2023290118
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
He C;Liu Y;Huang Z;Yang Z;Zhou T;Liu S;Hao Z;Wang J;Feng Q;Liu Y;Cao Y;Liu X
视网膜病变是致盲的主要原因，迫切需要开发有效的治疗方法。在这里，我们定义了一个前所未有的小胶质细胞亚群，负责在缺氧条件下引起视网膜病变。机制研究证实了缺氧诱导的视网膜小胶质细胞坏死性凋亡的信号通路，即，缺氧-RIP 1-RIP 3-MLKL信号传导轴，触发FGF 2的爆炸性释放，其转而诱导视网膜新生血管形成。同时靶向坏死性视网膜病变-FGF 2途径和VEGF可产生治疗视网膜病变的协同作用。基于我们的研究结果，我们提出了坏死性小胶质细胞诱导视网膜血管生成的概念，并强调了有效治疗视网膜病变的联合疗法。视网膜新生血管是人类严重视力丧失的主要原因，而小胶质细胞激活驱动的血管生成的分子机制仍然未知。使用单细胞RNA测序，我们确定了一个名为sMG 2的小胶质细胞亚群，其高度表达坏死性凋亡相关基因Rip 3和Mlkl。遗传和药理学的功能丧失表明，缺氧诱导的小胶质细胞活化致力于通过RIP 1/RIP 3介导的途径坏死性凋亡。Rip 3基因的特异性缺失显著降低了小胶质细胞视网膜新生血管的形成。此外，缺氧通过RIP 3介导的坏死性凋亡诱导小胶质细胞中大量FGF 2的爆发性释放。重要的是，阻断小胶质细胞坏死-FGF 2轴的信号传导成分在很大程度上消融了视网膜血管生成，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，针对小胶质细胞坏死性凋亡轴是视网膜新生血管疾病的抗血管生成治疗。
Retinopathy is the leading cause of blindness, and development of effective therapy is urgently needed. Here, we defined an unprecedented subgroup of microglia that is responsible for causing retinopathy under hypoxia. Mechanistic studies demonstrated the signaling pathway of hypoxia-induced necroptosis of retinal microglia, i.e., the hypoxia–RIP1–RIP3–MLKL signaling axis, triggered an explosive release of FGF2, which in its turn to induce retinal neovascularization. Simultaneous targeting of necroptosis–FGF2 pathway and VEGF produces synergistic effects for treating retinopathy. On the basis of our findings, we propose a concept of necroptotic microglia-induced retinal angiogenesis and highlight a combination therapy for effective treatment of retinopathy. 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.
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影响因子：
17.1
作者：
Sidman RL;Li J;Lawrence M;Hu W;Musso GF;Giordano RJ;Cardó-Vila M;Pasqualini R;Arap W
通讯作者：
Arap W
小胶质细胞坏死性凋亡通过 TLR4 激活导致神经炎症和视网膜变性
影响因子：
12.4
作者：
Huang Z;Zhou T;Sun X;Zheng Y;Cheng B;Li M;Liu X;He C
通讯作者：
He C
影响因子：
4.8
作者：
Steringer, Julia P.;Bleicken, Stephanie;Nickel, Walter
通讯作者：
Nickel, Walter
影响因子：
64.5
作者：
Li J;McQuade T;Siemer AB;Napetschnig J;Moriwaki K;Hsiao YS;Damko E;Moquin D;Walz T;McDermott A;Chan FK;Wu H
通讯作者：
Wu H
影响因子：
2.9
作者：
Reemst K;Noctor SC;Lucassen PJ;Hol EM
通讯作者：
Hol EM