Abstract
Purpose :
In age-related macular degeneration (AMD), inflammation is a major factor in disease progression. We and others have shown that inflammasome activation through the upregulation of the cGAS/STING pathway induces inflammatory changes and oxidative stress during AMD pathogenesis. In this study, we examine whether modulating the STING signaling pathway in a well-characterized mouse model of AMD could effectively impede the progression of the disease.
Methods :
In this study, we used Cryba1 KO, Sting KO, and WT (as control) mice and generated Cryba1/Sting dKO mice (by breeding Sting KO to Cryba1 KO). H&E staining was performed on eye sections from 10-month-old WT, Cryba1 KO, Sting KO, and Cryba1/Sting dKO mice to examine structural changes. RPE morphological changes were investigated in 10-month-old mice using ZO-1 immunostaining on flat mounts. STING, IL-1b, SOD1, and CAT levels in RPE lysates were quantified by western blotting.
Results :
The H&E staining from 10-month-old Cryba1 KO mice showed thinning of the RPE layer (patchy appearance) along with intermittent localization of RPE cells towards the outer segment layer. These changes were not observed in age-matched Sting KO and Cryba1/Sting dKO mice. Furthermore, western blot analysis showed that dKO RPE cells have no STING expression and reduced levels of IL-1b, SOD, and CAT compared to Cryba1 KO RPE cells, indicating rescue of inflammatory and oxidative stress mediators upon ablation of STING.
Conclusions :
Our data provides evidence that knocking out STING in a mouse model of AMD can rescue inflammation, oxidative stress, and RPE morphology changes. Thus, our study shows that targeting STING could be a novel therapy for AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.