ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets.

IF 5.3 2区医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2024-07-18 DOI:10.1186/s13395-024-00347-1

Yuehong Chen, Huan Liu, Zhongling Luo, Jiaqian Zhang, Min Dong, Geng Yin, Qibing Xie

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Abstract

Background: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM.

Methods: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro.

Results: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins.

Conclusion: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.

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ASM 可调节天真 CD4 + T 细胞分化为 Th17 和 Treg 亚群，是皮肌炎的治疗靶点。

背景：本研究旨在探讨酸性鞘磷脂酶（ASM）参与皮肌炎（DM）病理学的过程，使其成为DM的潜在治疗靶点：本研究旨在探讨酸性鞘磷脂酶（ASM）在皮肌炎（DM）病理中的参与，使其成为DM的潜在治疗靶点：方法：纳入DM患者和健康对照组（HCs），评估ASM的血清水平和活性，并探讨ASM与临床指标之间的关联。随后，我们利用ASM基因敲除和野生型小鼠建立了肌炎小鼠模型，以研究ASM在病理中的重要作用，并评估ASM抑制剂阿米替林的治疗效果。此外，我们还研究了体内和体外针对ASM的潜在治疗机制：结果：共纳入 58 名 DM 患者和 30 名 HCs。发现DM患者的ASM水平明显高于HC，中位值（四分位数）分别为2.63（1.80-4.94）纳克/毫升和1.64（1.47-1.96）纳克/毫升。DM 患者血清中的 ASM 活性明显高于 HC 患者。此外，血清中的ASM水平与疾病活动性和肌肉酶水平存在相关性。敲除ASM或使用阿米替林治疗可改善疾病的严重程度，重新平衡CD4 T细胞亚群Th17和Treg，并减少其分泌的细胞因子的产生。随后的研究发现，以ASM为靶点可以调节相关转录因子和关键调控蛋白的表达：结论：ASM 通过调节幼稚 CD4 + T 细胞的分化参与了 DM 的病理过程，可以成为潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.