Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice. (October 2019)

• Record Type: Journal Article
• Authors: Wu, Jian; Sun, Ping; Chen, Qi; Sun, Yong; Shi, Ming; Mang, Ge; Yu, Shan; Zheng, Yang; Li, Zhaoying; Sun, Meng; Fang, Shaohong; Zhang, Yongxiang; Tian, Jinwei; Mingyan, E.; Zhang, Maomao; Yu, Bo
• Is Part Of: Journal of molecular and cellular cardiology. Volume 135(2019)
• Page Start: 134
• Page End: 148
• Publication Date: 2019-10
• Subjects: Dilated cardiomyopathy -- Glycolytic metabolism -- T-cell; 2-DG 2-deoxy-d-glucose -- AT adoptive transfer -- BrdU bromodeoxyuridine -- CFA complete Freund's adjuvant -- DCM dilated cardiomyopathy -- ECAR extracellular acidification rate -- LVEDD left ventricular end diastolic diameter -- LVEF left ventricular ejection fraction -- LVESD left ventricular end systolic diameter -- MetPA metabolic pathway analysis -- MyHCα alpha-myosin H-chain -- OCR oxygen consumption rate -- OXPHOS oxidative phosphorylation -- PMA phorbol 12-myristate 13-acetate -- PBMC peripheral blood mononuclear cells; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.08.002
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4 + T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4 + T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-d -glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4 + T-cell immunological status. Adoptive transfer of CD4 + T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4 + T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.