Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.
Department of Medicine, Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN 37232.
J Immunol. 2021 Mar 15;206(6):1127-1139. doi: 10.4049/jimmunol.2001029. Epub 2021 Feb 8.
T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17-producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4- and IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.
效应 T 细胞促进哮喘患者的炎症，Th2 和 Th17 CD4 T 细胞都与疾病的严重形式有关。然而，在气道炎症的调控中，这些细胞的代谢表型和依赖性仍知之甚少。在这项研究中，我们发现哮喘患者的支气管肺泡灌洗液中有升高的葡萄糖和谷氨酰胺代谢标志物。此外，与健康对照组相比，通过质谱流式细胞术分析，哮喘患者的外周血 T 细胞广泛高表达代谢蛋白。因此，我们假设葡萄糖和谷氨酰胺代谢促进过敏性气道炎症。我们在两种气道炎症的小鼠模型中测试了这一假设。用 提取物致敏的小鼠肺部的 T 细胞通过单细胞 RNA 测序显示出氧化和葡萄糖代谢升高的遗传特征。当在产生 IL-17 的细胞中测量蛋白水平时，这一结果最为明显，并且当用屋尘螨加 LPS 诱导气道炎症时，这一结果得到了重现，这一模型导致了大量产生 IL-4 和 IL-17 的 T 细胞。重要的是，体内抑制葡萄糖转运蛋白 1 或谷氨酰胺酶可减弱屋尘螨+LPS 嗜酸性粒细胞增多、T 细胞细胞因子产生和气道高反应性，并增强地塞米松的免疫抑制特性。这些数据表明，T 细胞在体内诱导标志物以支持气道炎症中的代谢，并且这与炎症细胞因子的产生相关。靶向代谢途径可能为保护免受疾病和增强类固醇治疗效果提供新的方向。
