Department of Neurology and Pain Treatment, Neuromuscular Center, Center for Translational Medicine, Immanuel Klinik Rüdersdorf, University Hospital of the Brandenburg Medical School, 15562 Rüdersdorf bei Berlin, Germany.
Faculty of Health Sciences Brandenburg, Brandenburg Medical School, 15562 Rüdersdorf bei Berlin, Germany.
Int J Mol Sci. 2023 Jun 26;24(13):10675. doi: 10.3390/ijms241310675.
Inclusion body myositis (IBM) is a chronic, mostly treatment-resistant, inflammatory myopathy with a pathology that centers around specific interactions between inflammation and protein accumulation. The study aimed to identify the inflammasome as a key event in the complex network of pathomechanisms. Regulation of the inflammasome was assessed in a well-established pro-inflammatory cell culture model using human myoblasts and primary human myotubes. By quantitative PCR, western blot and immunocytochemistry, inflammasome markers including NLRP3 were assessed in muscle cells exposed to the cytokines IL-1β and IFN-γ. The data were corroborated by analysis of muscle biopsies from patients with IBM compared to other myositis subtypes. In the cell culture model of IBM, the NLRP3 inflammasome was significantly overexpressed, as evidenced by western blot ( = 0.03) and quantitative PCR ( < 0.01). Target genes that play a role in inflammasome assembly, T-cell migration, and MHC-I expression ( = 0.009) were highly co-upregulated. NLRP3 was significantly overexpressed in muscle biopsies from IBM samples compared to disease controls ( = 0.049), including other inflammatory myopathies. Due to the extraordinary features of the pathogenesis and the pronounced upregulation of NLRP3 in IBM, the inflammasome could serve as a key molecule that drives the inflammatory cascade as well as protein accumulation in the muscle. These data can be useful for future therapeutic developments.
包涵体肌炎（IBM）是一种慢性、多数治疗抵抗、炎症性肌病，其病理学以炎症和蛋白质积累之间的特定相互作用为中心。本研究旨在确定炎症小体作为发病机制复杂网络中的关键事件。使用人成肌细胞和原代人肌管，在成熟的促炎细胞培养模型中评估炎症小体的调节。通过定量 PCR、western blot 和免疫细胞化学，评估了在暴露于细胞因子 IL-1β和 IFN-γ的肌肉细胞中炎症小体标志物（包括 NLRP3）。通过与其他肌炎亚型的 IBM 患者肌肉活检的分析，对数据进行了验证。在 IBM 的细胞培养模型中，NLRP3 炎症小体明显过表达，这一点通过 western blot（ = 0.03）和定量 PCR（ < 0.01）得到证实。在炎症小体组装、T 细胞迁移和 MHC-I 表达中起作用的靶基因（ = 0.009）高度协同上调。与疾病对照（ = 0.049）相比，包括其他炎症性肌病在内，来自 IBM 样本的肌肉活检中 NLRP3 明显过表达。由于发病机制的特殊特征和 IBM 中 NLRP3 的明显上调，炎症小体可以作为驱动炎症级联反应以及肌肉中蛋白质积累的关键分子。这些数据可能对未来的治疗发展有用。
