STING mediates retinal lesion induced by cytosolic accumulation of damage DNA

Abstract

Purpose : Chronic inflammation plays an important role in the pathogenesis of Age related Macular Degeneration (AMD). One of the most pronounced triggers of chronic inflammation and cellular senescenceis the accumulation of damaged nuclear DNA (nDNA), especially in age-related conditions. Dnase2a is an enzyme located in lysosome and responsible for degradation of damaged DNA. We’ve discovered that knock out Dnase2 in micecauses the accumulation of damaged DNA in retinapigment epithelium (RPE) and leads to retinal morphology changes and impaired function featuring in AMD. Since STING (STimulator of Interferon Genes) is a DNA sensor, we hypothesize that knock out STING can block retinal lesion induced by the accumulation of damaged DNA.

Methods : To determine if the AMD-like retina lesion induced by Dnase2 deficiency is alleviated by STING modulation, both Dnase2^−/−mice and the double knockout mice (DKO, Sting^−/− Dnase 2^−/−)were examined by fundus photography and Optical Coherence Tomography (OCT). Furthermore, the mice were analyzed by full-field electroretinography (ERG) for light and dark response. Epi-fluorescent and electron microscopy were used to measure histological changes in the retina.

Results : Fundoscopy and OCT analyses showed that the DKO mice have significantly less drusen-like deposits beneath or above the RPE at 1 year of age in comparison of Dnase2^-/- mice. OCT detected DKO mice retina thicker outer nuclear layer and inner segment layer compared to Dnase2^−/−mice. In addition, electron microscopy revealed basal laminar deposits, a thickening of the Bruch’s membrane, a reduction in the basal infoldings of the RPE plasma membrane, vacuolization in RPE cells, and the loss of photoreceptors and RPE cells were significantly less observed in DKO mice compared to Dnase2^−/−mice. To assess the function of the retina, scotopic electroretinogram (ERG) was performed in both stains. A testing protocol with light stimuli of 3,000 and 10,000 cd*s/m²showed that both amplitudes of a and b wave were increased in response to each light stimulus in DKO mice compared to Dnase2^−/−mice.

Conclusions : Our results indicate that both retinal morphology changes and impaired function in Dnase2^−/−mice are alleviated by STING knock out. These indicate that STING mediates cytosolic accumulation of damage DNA to induce retinal lesion. This study will contribute to explore the novel therapeutic target for AMD.

This is a 2020 ARVO Annual Meeting abstract.