Small Extracellular Vesicles Released from ARPE-19 Cells Grown under Diabetic Retinopathy Conditions Promote NLRP3 Inflammasome Activation

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that forms part of the innate immune system. Recent studies have shown that the inflammasome pathway is upregulated in diabetic retinopathy (DR), resulting in breakdown of the retinal pigment epithelium (RPE) barrier. It has been hypothesized that small extracellular vesicles (sEVs) may transport inflammasome-related cargo between cells, which in turn contributes to the DR pathogenesis. The aim of this study was to investigate whether sEVs released from ARPE-19 cells grown under basal, DR-like conditions, and DR-like conditions with Peptide 5 treatment differ in inflammasome cargo and uptake. Additionally, the effects of the released sEVs on inflammasome activation in ARPE-19 cells, as well as their effect on vascular growth in a choroidal explant model, were investigated. Results demonstrated that sEVs from ARPE-19 cells grown under DR-like conditions carried increased inflammasome-related cargo and promoted NLRP3 inflammasome activation in recipient cells and tissues. Conversely, sEVs released from cells grown under basal and DR-like conditions with Peptide 5 treatment carried less inflammasome-related cargo. This research provides insights into the role of sEVs in the DR pathogenesis and suggests the potential therapeutic use of certain sEVs in treating DR.