Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200437, China.
Acta Neuropathol Commun. 2024 May 16;12(1):76. doi: 10.1186/s40478-024-01793-0.
Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2'3'-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.
活化的小胶质细胞在驱动视网膜感光细胞变性相关的神经炎症中发挥重要作用。控制小胶质细胞的促炎激活有望减轻感光细胞变性的进展。我们之前的研究表明,预先在光损伤前给予具有抗氧化和抗炎作用的天然类黄酮糖苷化合物——圣草酚,可以预防光氧化应激诱导的视网膜感光细胞变性和神经炎症反应。然而,圣草酚对感光细胞变性过程中小胶质细胞介导的神经炎症的直接影响尚不清楚。在验证了圣草酚在 LPS 刺激的 BV-2 细胞中的抗炎作用后,我们的结果进一步表明,光损伤后给予圣草酚治疗减轻了感光细胞的损失,并减轻了视网膜的功能下降。同时,光损伤后给予圣草酚治疗降低了光照射视网膜中的神经炎症反应和小胶质细胞的激活。就小胶质细胞激活而言,圣草酚减轻了 DNA 刺激的 BV-2 细胞中的促炎反应,并降低了 DNA 刺激的 BV-2 细胞中 2'3'-cGAMP 的产生。此外,圣草酚被证明可以直接与 cGAS 相互作用,并在无细胞体系中抑制 cGAS 的酶活性。总之,本研究首次表明 DNA 传感器 cGAS 是圣草酚的直接靶标。圣草酚可有效减轻 DNA 刺激的 cGAS 介导的小胶质细胞促炎激活,这可能有助于圣草酚抑制神经炎症和缓解神经炎症引发的感光细胞变性的治疗效果。