Chen Ziyi, Vaeth Martin, Eckstein Miriam, Delgobo Murilo, Ramos Gustavo, Frantz Stefan, Hofmann Ulrich, Gladow Nadine
University Hospital Würzburg, Department of Internal Medicine I, Würzburg, Germany.
Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University of Würzburg, Würzburg, Germany.
Eur J Pharmacol. 2023 Apr 15;945:175552. doi: 10.1016/j.ejphar.2023.175552. Epub 2023 Feb 2.
Increased aerobic glycolysis is a metabolic hallmark of proinflammatory leukocytes including macrophages and T cells. To take up glucose from the environment and fuel glycolysis, activated leukocytes upregulate the glucose transporter GLUT1. The orally bioavailable selective GLUT1 inhibitor BAY-876 was developed primarily as an anti-tumor drug. Our study assessed its activity on activated macrophages and CD4 T cells. BAY-876 significantly attenuated glucose uptake by cultured CD4 T cells and macrophages by 41% and 15%, respectively. Extracellular flux analysis of activated CD4 T cells in vitro showed that BAY-876 significantly decreases glycolytic proton flux rate and lactate production, effects that are accompanied by an increased oxidative phosphorylation-mediated ATP production rate, leaving intracellular ATP levels per cell unchanged. However, GLUT1 inhibition reduced CD4 T cell proliferation without compromising cell viability and reduced IFN-γ secretion by 20%. Moreover, TNF secretion from macrophages was reduced by 27%. We conclude that GLUT1-specific inhibitors, like BAY-876, deserve further in vivo testing in a broad range of (auto-) inflammatory disease models.
有氧糖酵解增加是包括巨噬细胞和T细胞在内的促炎白细胞的代谢特征。为了从环境中摄取葡萄糖并为糖酵解提供能量，活化的白细胞会上调葡萄糖转运蛋白GLUT1。口服生物可利用的选择性GLUT1抑制剂BAY-876主要作为一种抗肿瘤药物开发。我们的研究评估了其对活化巨噬细胞和CD4 T细胞的活性。BAY-876分别使培养的CD4 T细胞和巨噬细胞的葡萄糖摄取显著减少41%和15%。体外活化的CD4 T细胞的细胞外通量分析表明，BAY-876显著降低糖酵解质子通量率和乳酸生成，这些效应伴随着氧化磷酸化介导的ATP生成率增加，而每个细胞的细胞内ATP水平保持不变。然而，GLUT1抑制降低了CD4 T细胞增殖，而不影响细胞活力，并使IFN-γ分泌减少20%。此外，巨噬细胞的TNF分泌减少了27%。我们得出结论，像BAY-
