Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Research Center of Ion Channelopathy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Cardiovasc Res. 2023 Jun 13;119(6):1377-1389. doi: 10.1093/cvr/cvad029.
CD4+ T cells are the major drivers of cardiac-specific autoimmunity in myocarditis, specifically Th1, Treg, and most significant Th17 cells. But the molecular mechanisms of their activation remain unclear. We aimed to elucidate the regulatory role of phosphoglycerate kinase 1 (PGK1) in CD4+ T cells and experimental autoimmune myocarditis (EAM).
EAM was induced in BALB/c mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Single-cell sequencing analysis found that glycolysis and PGK1 expression were elevated in cardiac CD4+ T and Th17 cells from myocarditis mice. Mice treated with PGK1 inhibitor NG52 showed less cardiac inflammation and fibrosis and better contractile function, as well as reduced cardiac infiltrating Th17 and Th1 cells and increased proportion of Treg. NG52 suppressed CD4+ T cell activation and differentiation of mice and myocarditis patients in vitro. Mechanistically, inhibition of PGK1 suppressed glycolytic activity and decreased pyruvate dehydrogenase kinase 1 (PDHK1) phosphorylation, thereby increasing reactive oxygen species (ROS) production in mitochondria and thus preventing Th17 cell differentiation.
PGK1 may act as a key metabolic regulator of CD4+ T cell differentiation and regulates Th17 cell differentiation by regulating glycolysis and the PDHK1-ROS axis. Targeting PGK1 might be a promising strategy for the treatment of myocarditis.
CD4+T 细胞是心肌炎中心脏特异性自身免疫的主要驱动因素，特别是 Th1、Treg 和最重要的 Th17 细胞。但它们的激活分子机制仍不清楚。我们旨在阐明磷酸甘油酸激酶 1（PGK1）在 CD4+T 细胞和实验性自身免疫性心肌炎（EAM）中的调节作用。
通过皮下注射α肌球蛋白重链肽在完全弗氏佐剂中乳化，在 BALB/c 小鼠中诱导 EAM。单细胞测序分析发现，心肌炎小鼠心脏 CD4+T 和 Th17 细胞中的糖酵解和 PGK1 表达升高。用 PGK1 抑制剂 NG52 处理的小鼠表现出较少的心脏炎症和纤维化以及更好的收缩功能，以及减少心脏浸润的 Th17 和 Th1 细胞和增加 Treg 的比例。NG52 抑制了 CD4+T 细胞的激活和体外心肌炎患者的分化。从机制上讲，抑制 PGK1 抑制糖酵解活性并降低丙酮酸脱氢酶激酶 1（PDHK1）磷酸化，从而增加线粒体中活性氧（ROS）的产生，从而阻止 Th17 细胞分化。
PGK1 可能是 CD4+T 细胞分化的关键代谢调节因子，并通过调节糖酵解和 PDHK1-ROS 轴调节 Th17 细胞分化。靶向 PGK1 可能是治疗心肌炎的一种有前途的策略。
