Crosstalk between metabolism and inflammation in dry age-related macular degeneration

Abstract

Purpose : The dry form of age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly, has now been established as a multifactorial disease. Cellular metabolic alterations and chronic inflammation have been identified as two major pathological factors that contribute to the progression of dry AMD. In this study we evaluated the crosstalk between metabolic changes and inflammation induction in a mouse model that shows a dry AMD-like phenotype with the intent to target specific molecules in a pathway that would rescue both the metabolic insult and inflammation, thereby halting the progression of the disease.

Methods : RNAseq analysis was performed on RPE cells from cultured wild type RPE explants overexpressing βA1-, βA3- or βA3/A1-crystallin via adenoviral RFP constructs. To compare the metabolic gene profile/intermediates in the RPE cells at the early and advanced stages of disease progression in a mouse model, scRNAseq (cells from the sub-retinal space) and metabolomics/lipidomics (RPE cells) analyses were performed on 3, 10 and 15 month old Cryba1-floxed and cKO mice; data were confirmed with western blotting. βA3 KO and Cryba1 cKO mice were fed a high fat diet (HFD) to induce metabolic stress and resulting changes in signaling mediators and histopathology assessed.

Results : Metabolomics studies revealed a significant increase in the levels of intermediates known to induce mTORC1 signaling, like aspartate and betaine, in cKO RPE relative to controls. Lipidomic profiling showed elevated fatty acids (FAs) in cKO RPE, owing to the activation of the mTORC1-dependent FA synthesis pathway. We identified IL-17 signaling pathway activation as the link between these metabolic changes and chronic inflammation induction in the RPE of our mouse model during disease progression. Further, HFD treatment in our mouse models exacerbated the alterations in IL-17 levels and FA synthesis, and induced lipid droplet accumulation in the RPE cells.

Conclusions : We have now established the onset of IL-17 mediated inflammatory signaling as the link between cellular metabolic alterations and chronic inflammation in a mouse model of dry AMD. It is known that IL-17 is upregulated in the RPE of human AMD patients. Hence, targeting IL-17 and/or molecules of this signaling pathway could be an avenue for future therapeutic interventions to delay the progression of dry AMD.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.