Academic Unit of Ophthalmology, Translational Health Sciences, Bristol Medical School.
School of Cellular and Molecular Medicine, and.
JCI Insight. 2021 Apr 22;6(8):129429. doi: 10.1172/jci.insight.129429.
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.
视网膜色素上皮细胞代谢在免疫激活后如何被调节以维持视网膜内稳态和视网膜功能仍未解决。我们使视网膜色素上皮细胞（RPE）暴露于几种应激信号，特别是 Toll 样受体刺激，并发现 RPE 具有根据不同免疫刺激物改变其代谢偏好的能力，即有氧糖酵解或氧化葡萄糖代谢。我们已经确定白细胞介素-33（IL-33）是一个关键的代谢检查点，它拮抗瓦博格效应，以确保 RPE 的功能稳定性。IL-33 作为线粒体代谢的关键调节剂的鉴定表明，细胞因子的作用超出了其细胞外“警报素”活性。IL-33 通过促进氧化丙酮酸分解代谢来控制 RPE 中的线粒体呼吸。我们还揭示，在缺乏 IL-33 的情况下，线粒体功能下降，由此产生的生物能量转换与改变的线粒体形态一致。我们的数据不仅阐明了 RPE 对免疫应激物的线粒体呼吸激活的分子途径，而且揭示了核内固有 IL-33 作为代谢检查点调节剂的潜在新作用。
