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.
Highlights
The retina is referred to as an “immune-privileged” tissue, where immune homeostasis is maintained through hematopoietic immune cells, such as microglia, and immune-competent tissue-resident cells, such as the retinal pigment epithelium (RPE) [1]
Stimulation of RPE by LPS, a potent ligand of TLR4, promoted a substantial increase (1.5-fold) in the extracellular acidification rate (ECAR) relative to resting controls (Figure 1A) accompanied by a decrease in oxygen consumption rate (OCR) in human RPE cells (ARPE-19) (Figure 1B). These data imply increased aerobic glycolysis in LPS-stimulated ARPE-19 cells (Figure 1C), and this was supported by an increase in glucose consumption (Figure 1D)
RPE stress and metabolic alterations including mitochondrial dysfunction have been demonstrated to be implicated in retinal diseases [6, 30]
Summary
The retina is referred to as an “immune-privileged” tissue, where immune homeostasis is maintained through hematopoietic immune cells, such as microglia, and immune-competent tissue-resident cells, such as the retinal pigment epithelium (RPE) [1]. The RPE is highly differentiated and considered a postmitotic single-cell layer performing a host of functions critical to retinal homeostasis, including maintenance of the visual cycle and photoreceptor phagocytosis [2]. RPE cells are highly metabolically active while providing critical metabolic support through, for example, directional transport of glucose and lactate to fuel the outer retina and photoreceptors [3]. Defects in RPE metabolic and mitochondrial function, associated with low-grade inflammation or age-related decline, are associated with retinal degenerative diseases, including age-related macular degeneration (AMD) [4]. The causal link between RPE metabolic alterations and retinal function and disease remains unclear
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