1. Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors.
- Author
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Scott LM, Vincent EE, Hudson N, Neal C, Jones N, Lavelle EC, Campbell M, Halestrap AP, Dick AD, and Theodoropoulou S
- Subjects
- Animals, Cell Line, Cell Proliferation, Cell Survival, Energy Metabolism, Gene Knockdown Techniques, Glycolysis drug effects, Humans, Hydrogen Peroxide pharmacology, Interferon Inducers pharmacology, Interleukin-33 drug effects, Interleukin-33 genetics, Lipopolysaccharides pharmacology, Mice, Mice, Knockout, Mitochondria drug effects, Oxidants pharmacology, Oxidation-Reduction drug effects, Oxidative Stress, Poly I-C pharmacology, Primary Cell Culture, Pyruvic Acid metabolism, Cell Respiration physiology, Glycolysis physiology, Interleukin-33 metabolism, Mitochondria metabolism, Retinal Pigment Epithelium metabolism
- Abstract
It remains unresolved how retinal pigment epithelial cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed retinal pigment epithelium (RPE) to several stress signals, particularly Toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonizes the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular "alarmin" activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declined and resultant bioenergetic switching was aligned with altered mitochondrial morphology. Our data not only shed new light on the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors but also uncover a potentially novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.
- Published
- 2021
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