Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China; Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; The Cardiomyopathy Research Group at Fuwai Hospital.
Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China.
Int Immunopharmacol. 2023 Aug;121:110523. doi: 10.1016/j.intimp.2023.110523. Epub 2023 Jun 22.
Macrophages play an essential role in the pathogenesis of autoimmune myocarditis, but the molecular mechanism remains largely unknown. Here, the role of Stimulator of interferon gene (Sting) in autoimmune myocarditis was investigated. Six-week-old male BALB/c mice received two subcutaneous injections of 250 μg α-MyHC peptide to establish experimental autoimmune myocarditis (EAM). With single-cell RNA sequencing analysis of cardiac immune (Cd45) cells, Sting was found to initiate proinflammatory macrophage differentiation related to the acute EAM phase. Furthermore, proinflammatory macrophages contribute to the pathogenesis of EAM via hypoxia-inducible factor-1α (Hif1α). A higher expression level of Sting was detected in macrophages from myocarditis, which was positively correlated with Hif1α expression. Single-stranded DNA (ssDNA) accumulation in macrophages in myocarditis was observed in the hearts of EAM mice. Pharmacological blockade of STING by C-176 (a specific inhibitor) ameliorated the inflammatory response of EAM and reduced proinflammatory molecule (Ifn-β, Tnf-α, Ccl2, and F4/80) expression and Hif1α expression. In vitro studies revealed that ssDNA activated the expression of Sting; in turn, Sting accelerated proinflammatory molecule expression in mouse macrophages. Inhibition of Hif1α expression could reduce Sting-associated cardiac inflammation and proinflammatory molecule expression. In addition, the expression of STING and ssDNA accumulation in macrophages were observed in human autoimmune myocarditis heart samples. STING activated proinflammatory macrophage via HIF1A, promoting the development of autoimmune myocarditis. The STING signaling pathway might provide a novel mechanism of autoimmune myocarditis and serve as a potential therapeutic target for autoimmune myocarditis patients.
巨噬细胞在自身免疫性心肌炎的发病机制中发挥着重要作用，但分子机制在很大程度上仍不清楚。在这里，研究了干扰素基因刺激物（Sting）在自身免疫性心肌炎中的作用。将 6 周龄雄性 BALB/c 小鼠用 250μg α-MyHC 肽进行两次皮下注射，以建立实验性自身免疫性心肌炎（EAM）。通过心脏免疫（Cd45）细胞的单细胞 RNA 测序分析，发现 Sting 启动与急性 EAM 阶段相关的促炎巨噬细胞分化。此外，促炎巨噬细胞通过缺氧诱导因子-1α（Hif1α）促进 EAM 的发病机制。在心肌炎的巨噬细胞中检测到 Sting 的表达水平升高，与 Hif1α的表达呈正相关。在 EAM 小鼠的心脏中观察到心肌炎中巨噬细胞内的单链 DNA（ssDNA）积累。通过 C-176（一种特异性抑制剂）对 STING 的药理学阻断改善了 EAM 的炎症反应，降低了促炎分子（Ifn-β、Tnf-α、Ccl2 和 F4/80）的表达和 Hif1α 的表达。体外研究表明，ssDNA 激活了 Sting 的表达；反过来，Sting 加速了小鼠巨噬细胞中促炎分子的表达。抑制 Hif1α 的表达可以减少与 Sting 相关的心脏炎症和促炎分子的表达。此外，在人类自身免疫性心肌炎心脏样本中观察到巨噬细胞中 STING 的表达和 ssDNA 积累。STING 通过 HIF1A 激活促炎巨噬细胞，促进自身免疫性心肌炎的发展。STING 信号通路可能为自身免疫性心肌炎提供一种新的机制，并可能成为自身免疫性心肌炎患者的潜在治疗靶点。
