PDF(Pubmed)
Abstract：
Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
摘要：
特发性炎性肌病（IIM）是严重的自身免疫性疾病，其发病机理知之甚少，医疗需求未得到满足。这里,我们使用缺乏诱导型T细胞共刺激因子（Icos）的NOD雌性小鼠检查干扰素γ（IFNγ）的作用，先前已显示其发展为模仿人类疾病的自发性IFNγ驱动的肌炎。使用肌肉蛋白质组和空间转录组分析，我们揭示了这些小鼠中严重的肌纤维代谢失调。此外,我们报道了患病小鼠的肌肉线粒体异常和氧化应激。支持氧化应激的致病作用，用活性氧（ROS）缓冲化合物治疗缓解肌炎，保存的肌肉线粒体超微结构和呼吸，减少炎症。抗IFNγ治疗后，线粒体异常和氧化应激减少。在IIM患者和人类成肌细胞的体外研究中的进一步转录组学分析支持在小鼠中观察到的IFNγ和线粒体功能障碍之间的联系。这些结果表明，线粒体功能障碍，ROS和炎症在自我维持循环中相互联系，线粒体治疗和/或ROS靶向药物在肌炎中的开放前景。
