A specific RIP3 + subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism

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.