Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Invest Ophthalmol Vis Sci. 2024 Jul 1;65(8):16. doi: 10.1167/iovs.65.8.16.
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon gene (STING) pathway is a crucial cascade in the inflammatory response initiated by the recognition of cytosolic double-stranded DNA (dsDNA). The aim of this study was to evaluate the effect of STING inhibitor in murine choroidal neovascularization (CNV).
To investigate whether the cGAS-STING pathway is activated during CNV, CNV was induced using laser photocoagulation in male C57BL/6J mice. The expression of change of cGAS and STING during CNV development was confirmed by Western-blotting. H-151, a potent STING palmitoylation antagonist, was used as a STING inhibitor. H-151 was administered intravitreally immediately after laser induction. To confirm the role of the cGAS-STING pathway in CNV formation, we evaluated CNV size and performed fundus fluorescein angiography.
The expression levels of cGAS and STING were significantly upregulated in the RPE-choroid complex after CNV induction, and dsDNA merged with cGAS was observed in CNV lesions. Intravitreal administration of H-151 suppressed CNV development and fluorescent leakage from neovessels. In CNV lesions, the high expression of STING and cGAS was observed in infiltrating F4/80+ macrophages. H-151 administration attenuated downstream signals of the cGAS-STING pathway, including the phosphorylation of nuclear factor-κB, and downregulated the expression of interleukin 1β.
These findings support that the inhibition of cGAS-STING pathway treats abnormal ocular angiogenesis.
环鸟苷酸-腺苷酸合酶（cGAS）刺激干扰素基因（STING）通路是识别细胞浆双链 DNA（dsDNA）引发炎症反应的关键级联反应。本研究旨在评估 STING 抑制剂对小鼠脉络膜新生血管（CNV）的作用。
为了研究 cGAS-STING 通路在 CNV 期间是否被激活，我们采用激光光凝法在雄性 C57BL/6J 小鼠中诱导 CNV。通过 Western-blotting 证实了 cGAS 和 STING 在 CNV 发展过程中的变化表达。H-151 是一种有效的 STING 棕榈酰化拮抗剂，用作 STING 抑制剂。激光诱导后立即经玻璃体腔内给药。为了确认 cGAS-STING 通路在 CNV 形成中的作用，我们评估了 CNV 大小并进行眼底荧光血管造影。
CNV 诱导后，RPE-脉络膜复合物中 cGAS 和 STING 的表达水平显著上调，并且在 CNV 病变中观察到 dsDNA 与 cGAS 融合。玻璃体腔内给予 H-151 抑制了 CNV 的发展和新生血管的荧光渗漏。在 CNV 病变中，浸润性 F4/80+巨噬细胞中观察到 STING 和 cGAS 的高表达。H-151 给药减弱了 cGAS-STING 通路的下游信号，包括核因子-κB 的磷酸化，并下调了白细胞介素 1β的表达。
这些发现支持抑制 cGAS-STING 通路可治疗异常眼部血管生成。
