Metabolic reprogramming orchestrates CD4 T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice
Metabolic reprogramming orchestrates CD4 T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice
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代谢重编程协调 CD4 T 细胞免疫状态并恢复自身免疫诱导的扩张型心肌病小鼠的心脏功能障碍
DOI：
10.1016/j.yjmcc.2019.08.002
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发表时间：
2019
影响因子：
5
通讯作者：
Yu Bo
中科院分区：
文献类型：
--
作者：
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
细胞自身免疫反应，特别是由t细胞介导的细胞自身免疫反应，在扩张型心肌病（DCM）的免疫发病机制中起着至关重要的作用。代谢重编程直接控制t细胞功能，印记着不同的功能命运。然而，它对t细胞功能障碍和DCM的免疫发病机制的贡献尚不清楚。在这里，我们发现在DCM患者中，CD4+ t细胞表现出免疫功能障碍和基于细胞外酸化和耗氧率的糖酵解代谢重编程。在自身免疫诱导的DCM小鼠脾和心脏CD4+ t细胞中也观察到类似的结果。在体外，糖酵解抑制剂2-脱氧-d-葡萄糖（2-DG）逆转了t细胞功能障碍；因此，增高的代谢活性直接控制CD4+ t细胞的免疫状态。将DCM小鼠的CD4+ t细胞过继转移到正常受体可诱导心脏重塑和心脏t细胞功能障碍。引人注目的是，用2-DG预处理细胞可以消除这些影响，这表明部分由代谢重编程诱导的CD4+ t细胞功能障碍有助于心脏重塑。此外，microRNA let-7i通过直接靶向Myc调节DCM小鼠t细胞的代谢和功能。总的来说，我们的研究结果表明，代谢重编程发生在自身免疫诱导的DCM小鼠和患者的t细胞中。此外，我们的研究结果强调糖酵解代谢是t细胞功能障碍和DCM免疫发病机制的关键因素。我们的数据将代谢调节定位为t细胞功能的中心整合器，代表了对抗自身免疫介导的DCM进展的有希望的策略。
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.