Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Sci Signal. 2020 Oct 27;13(655):eaay9217. doi: 10.1126/scisignal.aay9217.
Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell-mediated autoimmunity that mimics multiple sclerosis (MS). T17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17-producing T17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of T17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.
促进丙酮酸激酶同工酶 PKM2 代谢活性的小分子，如 TEPP-46 和 DASA-58，可限制肿瘤发生和炎症。为了了解这些化合物如何改变 T 细胞功能，我们在模拟多发性硬化症 (MS) 的 T 细胞介导自身免疫小鼠模型中评估了它们的治疗活性。T17 细胞被认为通过产生两种促炎细胞因子：白细胞介素 17 (IL-17) 和 GM-CSF 来协调 MS 病理学。我们发现，TEPP-46 和 DASA-58 均可抑制产生 IL-17 的 T17 细胞的发育，但增加了产生 GM-CSF 的细胞数量。这种转变将疾病病理学从脊髓转向大脑。此外，我们发现 PKM2 的激活会干扰 TGF-β1 信号转导，这对于 T17 和调节性 T 细胞的发育是必需的。总之，我们的数据阐明了 PKM2 激活剂在 MS 样疾病中的治疗潜力，以及这些药物如何改变 T 细胞功能。
