IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis
IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis
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DOI：
10.1007/s00401-017-1731-9
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发表时间：
2017-10-01
影响因子：
12.7
通讯作者：
Geny, Bernard
中科院分区：
文献类型：
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作者：
Meyer, Alain;Laverny, Gilles;Geny, Bernard
皮肌炎 (DM) 是一种与骨骼肌中 I 型干扰素 (IFN) 信号增强相关的自身免疫性疾病，但肌肉功能障碍和炎症持续的机制仍不清楚。对早期未经治疗的 DM 肌肉的转录组分析表明，下调基因的主要簇与线粒体相关。组织化学、电子显微镜和原位氧描记分析显示线粒体异常，包括活性氧 (ROS) 产生增加和呼吸减少，这与运动能力低下和 I 型 IFN 特征相关。此外，发现 IFN-β 诱导人肌管中 ROS 的产生会导致线粒体功能障碍。重要的是，ROS 清除剂 N-乙酰半胱氨酸 (NAC) 可预防实验性自身免疫性肌炎小鼠模型中的线粒体功能障碍、I 型 IFN 刺激的转录水平、炎症细胞浸润和肌肉无力。因此，这些数据强调了线粒体和 ROS 在 DM 中的核心作用。由 IFN-β 诱导的 ROS 介导的线粒体功能障碍导致运动能力差。此外，线粒体功能障碍会增加ROS的产生，从而驱动I型IFN诱导的基因表达和肌肉炎症，从而可能使疾病自我维持。鉴于目前的 DM 治疗仅导致部分恢复并面临严重的不良事件（包括肌肉毒性），保护线粒体免受功能障碍可能会为 DM 开辟新的治疗途径。
Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-beta induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-beta induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.