Over Activation of IL-6/STAT3 Signaling Pathway in Juvenile Dermatomyositis.

IF 2.9 3区医学 Q2 RHEUMATOLOGY Rheumatology and Therapy Pub Date : 2024-10-01 Epub Date: 2024-07-29 DOI:10.1007/s40744-024-00699-6

Qi Zheng, Zhaoling Wang, Yejun Tan, Kun Zhu, Meiping Lu

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Abstract

Introduction: Juvenile dermatomyositis (JDM) is characterized by persistent non-purulent inflammation in the muscle and skin. The underlying mechanisms still remain uncertain. This study aims to elucidate the mechanism of interleukin-6 (IL-6) activation of Janus kinase/signal transducer and activator of transcription 3 pathway (JAK/STAT3), contributing to the pathogenesis of JDM.

Methods: Serum IL-6 levels were compared between 72 newly diagnosed patients with JDM and the same patient cohort in treatment remission. Single-cell RNA sequencing (scRNA-seq) was employed to identify differential signaling pathway expression in muscle biopsy samples from two patients with JDM and healthy controls. Immunohistochemistry was used to examine differences in STAT3 phosphorylation between JDM and control muscle tissues. In vitro, skeletal muscle cell lines were stimulated with IL-6, and the transcription levels of genes related to mitochondrial calcium channels were quantified via reverse transcription-polymerase chain reaction (RT-PCR). Reactive oxygen species (ROS) production was measured in both IL-6 treated and untreated groups. ROS levels were then compared between IL-6 receptor antagonist pre-treated skeletal muscle cells and untreated cells.

Results: IL-6 levels in newly onset patients with JDM were significantly higher compared to the same patient cohort in remission states (p < 0.0001). Serum IL-6 was significantly increased in patients with negative myositis specific antibody (MSA), positive melanoma differentiation associated protein 5 (MDA5) and positive nuclear matrix protein 2 (NXP2), yet not for JDM with positive transcriptional intermediary factor γ (TIF1γ), based on subgroup analysis. ScRNA-seq analysis of muscle biopsies from patients with MDA5-positive JDM and patients with MSA negative JDM revealed abnormal activation of the JAK/STAT3 pathway in skeletal myocytes, macrophages, and vascular endothelial cells. The phosphorylation levels of STAT3 were elevated in active JDM cases. Transcription of the calcium channel modulation gene sarcolipin (SLN) was significantly higher in JDM primary skeletal muscle cells compared to normal cells. In vitro, IL-6 enhanced SLN transcription and induced ROS production, and blocking the IL-6 receptor resulted in decreased ROS generation in skeletal muscle cells.

Conclusions: IL-6/JAK/STAT3 signaling pathway was abnormally activated in patients with JDM. IL-6 may be involved in the pathogenesis of muscle damage by triggering the development of calcium overload and production of ROS. Blockade of the IL-6/JAK/STAT3 pathway can be a potential treatment option for JDM, especially MDA5-positive patients and those who are negative for MSA.

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幼年皮肌炎中 IL-6/STAT3 信号通路的过度激活

简介幼年皮肌炎（JDM）的特点是肌肉和皮肤出现持续性非化脓性炎症。其潜在机制仍不明确。本研究旨在阐明白细胞介素-6（IL-6）激活 Janus 激酶/信号转导和激活剂转录 3 通路（JAK/STAT3）的机制，从而促进 JDM 的发病：方法：比较了72名新确诊的JDM患者和同一批治疗缓解期患者的血清IL-6水平。采用单细胞 RNA 测序（scRNA-seq）技术鉴定了两名 JDM 患者和健康对照组肌肉活检样本中不同信号通路的表达。免疫组化技术用于检测 JDM 和对照组肌肉组织中 STAT3 磷酸化的差异。在体外，用 IL-6 刺激骨骼肌细胞系，并通过反转录聚合酶链反应（RT-PCR）量化线粒体钙通道相关基因的转录水平。IL-6 处理组和未处理组都测量了活性氧（ROS）的产生。然后比较经 IL-6 受体拮抗剂预处理的骨骼肌细胞与未处理细胞的 ROS 水平：结果：与处于缓解状态的同组患者相比，新发 JDM 患者的 IL-6 水平明显较高（PJDM患者的IL-6/JAK/STAT3信号通路异常激活。IL-6可能通过引发钙超载和产生ROS参与了肌肉损伤的发病机制。阻断IL-6/JAK/STAT3通路可能是治疗JDM的一种选择，尤其是MDA5阳性和MSA阴性的患者。

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来源期刊

Rheumatology and Therapy RHEUMATOLOGY-

CiteScore

6.00

自引率

5.30%

发文量

审稿时长

6 weeks

期刊介绍： Aims and Scope Rheumatology and Therapy is an international, open access, peer reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world and health outcomes research around the discovery, development, and use of rheumatologic therapies. Studies relating to diagnosis, pharmacoeconomics, public health, quality of life, and patient care, management, and education are also welcomed. Areas of focus include, but are not limited to, rheumatoid arthritis, gout, gouty arthritis, psoriatic arthritis, osteoarthritis, juvenile idiopathic/rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, Pompe’s disease, inflammatory joint conditions, musculoskeletal conditions, systemic sclerosis, and fibromyalgia. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, case reports, trial protocols, communications and letters. 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