1. Therapeutic intervention in neuroinflammation for neovascular ocular diseases through targeting the cGAS-STING-necroptosis pathway.
- Author
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Ni B, Yang Z, Zhou T, Zhou H, Zhou Y, Lin S, Xu H, Lin X, Yi W, He C, and Liu X
- Subjects
- Animals, Humans, Mice, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Choroidal Neovascularization drug therapy, Signal Transduction drug effects, Signal Transduction physiology, Mice, Knockout, Diabetic Retinopathy metabolism, Nucleotidyltransferases metabolism, Nucleotidyltransferases genetics, Nucleotidyltransferases antagonists & inhibitors, Membrane Proteins metabolism, Membrane Proteins genetics, Membrane Proteins antagonists & inhibitors, Neuroinflammatory Diseases metabolism, Mice, Inbred C57BL
- Abstract
The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases., (© 2024. The Author(s).)
- Published
- 2024
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