Inflammatory adipose activates nutritional immunity leading to retinal dysfunction

Abstract

Purpose : Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the United States among those older than 50. Dysfunction and death of retinal pigment epithelial (RPE) cells are key to the pathogenesis. Previous work has shown that iron accumulates in the RPE of AMD eyes, and iron overload is sufficient to trigger RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown.

Methods : Herein, we use in vitro primary human RPE and in vivo mouse RPE studies, in addition to human single-cell RNAseq data from AMD cases and controls, to study an inflammatory mechanism of iron accumulation.

Results : Herein we show that high fat diet, an AMD risk factor, drives systemic and local inflammatory circuits upregulating interleukin 1β (IL-1β). IL-1β upregulates RPE iron importers and downregulates iron exporters. This, in turn, triggers RPE iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response, or CISR. Single cell RNAseq analysis of choroid and neurosensory retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages.

Conclusions : Together, these data suggest that obesity, through CISR, can lead to RPE iron accumulation in AMD.

This is a 2021 ARVO Annual Meeting abstract.