Small molecule SIRT1 activators counteract oxidative stress-induced inflammasome activation and nucleolar stress in retinal degeneration

Background: The nicotinamide adenosine dinucleotide-dependent deacetylase Sirtuin 1 (SIRT1) has been identified as a protective factor that inhibits the activation of nucleotide-binding and oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. However, whether pharmacological SIRT1 activators can protect retinal pigment epithelial (RPE) cells against oxidative and inflammatory injuries related to age-related macular degeneration remains to be explored. Methods: Two small molecule specific SIRT1 activators (SRT2104 and CAY10602) were tested, with resveratrol being used as a positive control. Mouse models with sodium iodate-induced retinal degeneration were constructed. ARPE-19 cells in culture were used for in vitro experiments. The effects of SIRT1 activators on H2O2induced ARPE-19 cell injury were determined by reactive oxygen species quantification, western blotting, flow cytometry and immunofluorescence staining. In vivo, the severity of retinal damage was assessed using flash electroretinography and histopathological analysis. Results: In vitro, SRT2104, CAY10602 and resveratrol significantly attenuated H2O2-induced cell death, nucleolar stress response, and reactive oxygen species accumulation. In H2O2-stimulated cells, SIRT1 activators reduced the level of NLRP3, inhibited the activation of caspase-1, and decreased the production of interleukin (IL)-1(3 and IL-18. The inhibitory effects of SIRT1 activators on caspase-1 activation and IL-1(3 production were blunted by SIRT1 gene silencing. In vivo, treatment with SRT2104 or CAY10602 in mice with sodium iodate-induced retinal degeneration markedly improved the retinal functions and reduced the loss of RPE cells. Conclusion: Our study suggests that small molecule SIRT1 activators are effective for protection of RPE cells against oxidative stress-induced NLRP3 inflammasome activation, highlighting potential applications in the treatment of macular degeneration associated RPE dysfunctions.