Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China.
Department of General Practice, West China Hospital, General Practice Medical Center, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China.
Skelet Muscle. 2024 Jul 18;14(1):16. doi: 10.1186/s13395-024-00347-1.
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.
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.
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.
ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.
本研究旨在探讨酸性鞘磷脂酶（ASM）在皮肌炎（DM）发病机制中的作用，为 DM 的治疗提供新靶点。
纳入 DM 患者和健康对照（HC），评估血清 ASM 水平和活性，并探讨 ASM 与临床指标的相关性。随后，采用 ASM 基因敲除和野生型小鼠建立肌炎模型，研究 ASM 在发病机制中的作用，并评估 ASM 抑制剂阿米替林的治疗效果。此外，我们还通过体内和体外靶向 ASM 研究了其潜在的治疗机制。
共纳入 58 例 DM 患者和 30 例 HC。与 HC 相比，DM 患者血清 ASM 水平显著升高，中位数（四分位数范围）分别为 2.63（1.80-4.94）ng/ml 和 1.64（1.47-1.96）ng/ml。DM 患者血清 ASM 活性明显高于 HC。此外，血清 ASM 水平与疾病活动度和肌酶水平相关。敲除 ASM 或用阿米替林治疗可改善疾病严重程度，使 Th17 和 Treg 细胞亚群平衡，并减少其分泌细胞因子的产生。进一步研究发现，靶向 ASM 可调节相关转录因子和关键调节蛋白的表达。
ASM 通过调节初始 CD4+T 细胞的分化参与 DM 的发病机制，可能成为潜在的治疗靶点。
