Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Front Immunol. 2023 Jul 7;14:1191815. doi: 10.3389/fimmu.2023.1191815. eCollection 2023.
Idiopathic inflammatory myopathies (IIMs), which are a group of chronic and diverse inflammatory diseases, are primarily characterized by weakness in the proximal muscles that progressively leads to persistent disability. Current treatments of IIMs depend on nonspecific immunosuppressive agents (including glucocorticoids and immunosuppressants). However, these therapies sometimes fail to regulate muscle inflammation, and some patients suffer from infectious diseases and other adverse effects related to the treatment. Furthermore, even after inflammation has subsided, muscle weakness persists in a significant proportion of the patients. Therefore, the elucidation of pathophysiology of IIMs and development of a better therapeutic strategy that not only alleviates muscle inflammation but also improves muscle weakness without increment of opportunistic infection is awaited. Muscle fiber death, which has been formerly postulated as "necrosis", is a key histological feature of all subtypes of IIMs, however, its detailed mechanisms and contribution to the pathophysiology remained to be elucidated. Recent studies have revealed that muscle fibers of IIMs undergo necroptosis, a newly recognized form of regulated cell death, and promote muscle inflammation and dysfunction through releasing inflammatory mediators such as damage-associated molecular patterns (DAMPs). The research on murine model of polymyositis, a subtype of IIM, revealed that the inhibition of necroptosis or HMGB1, one of major DAMPs released from muscle fibers undergoing necroptosis, ameliorated muscle inflammation and recovered muscle weakness. Furthermore, not only the necroptosis-associated molecules but also PGAM5, a mitochondrial protein, and reactive oxygen species have been shown to be involved in muscle fiber necroptosis, indicating the multiple target candidates for the treatment of IIMs acting through necroptosis regulation. This article overviews the research on muscle injury mechanisms in IIMs focusing on the contribution of necroptosis in their pathophysiology and discusses the potential treatment strategy targeting muscle fiber necroptosis.
特发性炎性肌病（IIM）是一组慢性和多样化的炎症性疾病，主要特征为近端肌肉无力，逐渐导致持续残疾。目前的 IIM 治疗依赖于非特异性免疫抑制剂（包括糖皮质激素和免疫抑制剂）。然而，这些治疗方法有时无法调节肌肉炎症，一些患者会遭受与治疗相关的传染病和其他不良反应。此外，即使炎症消退后，相当一部分患者仍存在肌肉无力。因此，需要阐明 IIM 的病理生理学，并开发出一种更好的治疗策略，不仅能缓解肌肉炎症，还能改善肌肉无力，而不会增加机会性感染。肌肉纤维死亡以前被认为是“坏死”，是所有 IIM 亚型的一个关键组织学特征，但其详细机制及其对病理生理学的贡献仍有待阐明。最近的研究表明，IIM 的肌肉纤维经历坏死性细胞死亡，这是一种新发现的细胞死亡形式，通过释放损伤相关分子模式（DAMPs）等炎症介质促进肌肉炎症和功能障碍。对 IIM 亚型多发性肌炎的鼠模型的研究表明，抑制坏死性细胞死亡或高迁移率族蛋白 B1（HMGB1）可改善肌肉炎症并恢复肌肉无力，后者是从经历坏死性细胞死亡的肌肉纤维中释放的主要 DAMPs 之一。此外，不仅是与坏死性细胞死亡相关的分子，还有线粒体蛋白 PGAM5 和活性氧物种也被证明参与肌肉纤维坏死性细胞死亡，这表明通过坏死性细胞死亡调节来治疗 IIM 的多个潜在治疗靶点候选物。本文综述了 IIM 中肌肉损伤机制的研究，重点关注坏死性细胞死亡在其病理生理学中的作用，并讨论了针对肌肉纤维坏死性细胞死亡的潜在治疗策略。
