Identification of age-related changes and intracellular DNA sensors in the retina, using single-cell transcriptomics

We identified age-related, cell-type specific transcriptional changes. Ageing rods have shown metabolic reprogramming, while ageing macroglia have shown a reactive gliosis phenotype. Genomic instability and increased proteostasis burden was found in ageing bipolar cells.

Meanwhile, the bidirectional communication between microglia and other retinal cells was also found to be altered in the ageing retina that favours a low-grade chronic inflammation (para-inflammation). To understand how inflammation is initiated in the ageing retina, we focused on retinal DNA sensing pathways. Intracellular DNA sensors initiate the host immune response by recognising cytosolic DNA derived from pathogen replication or endogenous nucleic acid released by damaged nuclei or mitochondria.

The retinal DNA sensing system requires further investigation. We established an expression profile of retinal intracellular DNA sensors. We further confirmed the expression of the adaptor protein of DNA sensing pathway, STING, in the retina.

We demonstrated that STING is critically involved in dsDNA-induced type I IFN response in microglia and RPE cells, but not in photoreceptors and Müller glia. An increased enrichment of DNA sensors was detected in microglia in the ageing retina. Significant increase of Sting expression was found in the ageing mouse neuroretina.

Studies have suggested the DNA sensing pathways connects genomic instability and inflammation during ageing. These results suggest that DNA sensors activation may be partially responsible for para-inflammation in the ageing retina.<br><br><i>Thesis is embargoed until 31 July 2028</i>.<br><br>