Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China.
Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Pharmacol Res. 2019 Aug;146:104269. doi: 10.1016/j.phrs.2019.104269. Epub 2019 May 9.
Autoimmune myocarditis is an immune-mediated myocardial injury that evolves into dilated cardiomyopathy (DCM). Protosappanin A (PrA), an immunosuppressive compound, induces immune tolerance in cardiac transplantation. However, whether PrA confers protective immunosuppression on experimental autoimmune myocarditis (EAM) is unknown. In this study, PrA treatment remarkably suppressed cardiac inflammatory cell infiltration and ameliorated cardiac remodeling in EAM mice. Additionally, PrA treatment reduced splenic T cells response, and induced expansion of immunosuppressive regulatory T cells (Tregs). Meanwhile, PrA induced the splenic dendritic cells (DCs) into a tolerogenic state with reduced co-stimulatory molecules, increased the production of tolerogenic cytokines in vivo. PrA also reprogrammed the metabolism of splenic DCs to a more glycolytic phenotype. To further investigate the effect of PrA on the functional and metabolic phenotype of DCs, the compound was added into the in vitro culture of MyHC-α-loaded DCs. These cells switched to a tolerogenic state and a metabolic profile similar to that found in cells during in ex vivo experiments. Treatment with glycolytic inhibitor 2-DG significantly reversed PrA-mediated DC tolerogenic properties, suggesting that glycolysis is indispensable for PrA-conditioned DCs to maintain their tolerogenic properties. Notably, PrA-conditioned DC vaccinations dampened EAM progress, and promoted Tregs expansion. Similarly, tolerogenic and metabolic patterns were also observed in PrA-modified human DC. In conclusion, PrA endows DC with a tolerogenic profile via glycolytic reprogramming, thereby inducing expansion of immunosuppressive Tregs, and preventing EAM progress. Our results suggested that PrA may confer immunosuppressive and protective effects on EAM by metabolically reprogramming DCs, which could contribute to the development of a new potential immunotherapy for the treatment of EAM and immune-related disorders.
自身免疫性心肌炎是一种免疫介导的心肌损伤，可发展为扩张型心肌病（DCM）。原七叶皂苷甲（PrA）是一种免疫抑制化合物，可在心脏移植中诱导免疫耐受。然而，PrA 是否对实验性自身免疫性心肌炎（EAM）具有保护免疫抑制作用尚不清楚。在这项研究中，PrA 治疗显著抑制了 EAM 小鼠的心脏炎性细胞浸润和心脏重构。此外，PrA 治疗减少了脾 T 细胞反应，并诱导了免疫抑制性调节性 T 细胞（Tregs）的扩增。同时，PrA 将脾树突状细胞（DC）诱导为具有低共刺激分子的耐受性状态，增加了体内耐受性细胞因子的产生。PrA 还重新编程了脾 DC 的代谢，使其向更糖酵解表型转变。为了进一步研究 PrA 对 DC 功能和代谢表型的影响，将该化合物添加到负载 MHC-α 的 DC 的体外培养中。这些细胞转变为耐受性状态，并且代谢特征与体外实验中发现的细胞相似。用糖酵解抑制剂 2-DG 处理可显著逆转 PrA 介导的 DC 耐受性特性，表明糖酵解对于 PrA 调节的 DC 维持其耐受性特性是必不可少的。值得注意的是，PrA 调节的 DC 疫苗接种可抑制 EAM 进展并促进 Tregs 扩增。同样，在 PrA 修饰的人 DC 中也观察到了耐受性和代谢模式。总之，PrA 通过糖酵解重编程赋予 DC 耐受性表型，从而诱导免疫抑制性 Tregs 的扩增，并防止 EAM 进展。我们的结果表明，PrA 通过代谢重编程 DC 可对 EAM 发挥免疫抑制和保护作用，这可能有助于开发用于治疗 EAM 和免疫相关疾病的新的潜在免疫疗法。
