Open AccessA specific RIP3 + subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism
Author(s) -
Chang He,
Yan Liu,
Zijing Huang,
Ziqi Yang,
Tian Zhou,
Sheng Liu,
Zhao-Zhe Hao,
Jing Wang,
Qiumin Feng,
Yizhi Liu,
Yihai Cao,
Xialin Liu
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2023290118
Subject(s) - necroptosis , microglia , retinal , hypoxia (environmental) , diabetic retinopathy , retinopathy , angiogenesis , retina , cancer research , neovascularization , signal transduction , biology , medicine , microbiology and biotechnology , neuroscience , immunology , ophthalmology , chemistry , programmed cell death , inflammation , endocrinology , biochemistry , apoptosis , organic chemistry , oxygen , diabetes mellitus
Significance 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.