PKM2-dependent metabolic reprogramming in CD4+ T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2018-06, Vol.96 (6), p.585-600
• Main Authors: Lü, Silin, Deng, Jiacheng, Liu, Huiying, Liu, Bo, Yang, Juan, Miao, Yutong, Li, Jing, Wang, Nan, Jiang, Changtao, Xu, Qingbo, Wang, Xian, Feng, Juan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apolipoprotein E; Arteriosclerosis; Atherosclerosis; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Cell activation; Endoplasmic reticulum; Glycolysis; Homocysteine; Human Genetics; Hyperhomocysteinemia; Inflammation; Interferon; Internal Medicine; Kinases; Lymphocytes; Lymphocytes T; Metabolism; Metabolites; Mice; Mitochondria; Molecular Medicine; Muscles; Original Article; Oxidative phosphorylation; Phosphorylation; Pyruvate kinase; Pyruvic acid; Rapamycin; Rodents; Signal transduction; siRNA; TOR protein; Transgenic mice; γ-Interferon
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-018-1645-6

Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE −/− mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4 + T cells. Mechanistically, Hcy-activated CD4 + T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4 + T cell IFN - γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2 fl/fl mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4 + T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-γ secretion. T cell-depleted apolipoprotein E-deficient (ApoE −/− ) mice adoptively transferred with PKM2-deficient CD4 + T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4 + T cell activation to accelerate early atherosclerosis in ApoE −/− mice. Key messages Metabolic reprogramming is crucial for Hcy-induced CD4 + T cell inflammatory activation. Hcy activates the glycolytic-lipogenic pathway in CD4 + T cells via PKM2. Targeting PKM2 attenuated HHcy-accelerated early atherosclerosis in ApoE −/− mice in vivo.