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Sofia Theodoropoulou, David Alexander Copland, Jian Liu, Andrew D Dick; Toll-like receptor activation of retinal pigment epithelial cells induces a glycolytic shift and increase of IL-33 expression.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):79.
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Age-related macular degeneration (AMD) is the predominant cause of irreversible blindness. Inflammation is recognized widely as an important player in its pathogenesis. The inflammasome responds to cell stress through pattern recognition receptors, including Toll-like receptors (TLRs). Interleukin-33 (IL-33), a member of the IL-1 family, induces inflammation via specific IL-1 receptor accessory protein and Toll-IL-1 receptor superfamily member ST2, and is closely associated with TH2 T cell responses. The aim of this study was to evaluate whether TLR activation in retinal pigment epithelial cells (RPE) alters metabolic status which in turn altered expression pattern and regulation of IL-33 in TLR-stimulated RPE.
Human and mouse RPE cells (ARPE-19 and B6-RPE07) were stimulated with different doses of LPS (TLR-4 ligand) or poly(I:C) (TLR-3 ligand) and their energy metabolism was assessed by measuring the levels of lactate, glucose consumption and the expression of glucose transporter Glut1. Expression profile of IL-33 was assessed by RT-PCR and Western blots.
Stimulation of RPE by TLR4 and TLR3 promoted an increase (by 20%) in the glycolytic rate relative to controls. Both the production of lactate, a metabolic end point of aerobic glycolysis, and glucose consumption increased after LPS or poly(I:C) stimulation of RPE in a dose and time dependent manner. As increased glycolysis requires greater usage of glucose, we found increased levels of Glut1 transcripts after TLR stimulation of RPE. Furthermore, TLR stimulation of RPE resulted in significant up-regulation of IL-33 expression. Treatment of both RPE cell lines with LPS or poly(I:C) increased levels of IL-33 transcripts and protein. RT- PCR analysis also showed increased ST2 expression, which suggests a functional IL-33/ST2 axis in retinal degeneration.
Our data pinpoint TLR-mediated metabolic transition to aerobic glycolysis (“Warburg” effect) as essential for RPE function, probably by influencing innate immunity status. In addition, IL-33 production was modulated after LPS or poly(I:C) stimulation in RPE cells, uncovering a role of IL-33/ST2 axis in RPE function. Our findings suggest novel potential therapeutic targets for diseases such as AMD.
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