Zhao Lijuan, Shen Chuyu, Xie Shasha, Zhou Junyu, Zhang Huali, Zhu Honglin, Li Yisha, Gao Siming
Department of Nephrology and Rheumatology, The Third Xiangya Hospital of Central South University, Changsha, PR China; Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, PR China.
Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
Int Immunopharmacol. 2023 Nov;124(Pt A):110803. doi: 10.1016/j.intimp.2023.110803. Epub 2023 Aug 23.
Dermatomyositis (DM) is the best known subtype of idiopathic inflammatory myopathies. The hallmarks of DM muscle pathology including microangiopathy, inflammatory infiltration, and perifascicular atrophy. Recent findings have revealed pathogenetic effects of myeloperoxidase (MPO) by causing oxidative damage and regulating abnormal immunity in multiple disease conditions. In this study, we aimed to explore the role of MPO in the pathogenesis of DM.
The peripheral blood mononuclear cell (PBMC) mRNA expression and DNA methylation of MPO were verified using real-time qPCR and bisulfite pyrosequencing, respectively. Plasma MPO levels were measured with enzyme-linked immunosorbent assay, and their relationships with clinical characteristics were analyzed. The expression and distribution of MPO in muscle were tested by immunofluorescence. Purified human native MPO protein was used to stimulate human dermal microvascular endothelial cells (HDMECs) and skeletal muscle myotubes. The cell viability, tube forming capacity, permeability, adhesion molecule expressions in HDMECs, and atrophy and programmed cell death pathways in myotubes were then observed.
MPO gene methylation was decreased, while mRNA expression and plasma levels were increased in DM. Plasma MPO of DM patients was positively correlated with serum creatine kinase (CK). MPO mainly distributed around endomysia capillaries and perifascicular atrophy in DM muscle biopsies, and was co-localized with CD4, CD8 T cells and CD19 B cells. MPO not only could influence the cell viability, tube forming capacity, permeability and expression of adhesion molecules (including ICAM 1, VCAM 1 and E-selectin) of HDMECs, but also could cause atrophy of myotubes.
Our study disclosed, for the first time, that MPO plays an important role in promoting inflammatory infiltration and inducing muscle damage in DM patients. MPO may be a potential biomarker for DM muscle involvement and MPO targeted drugs may be promising in DM treatment.
皮肌炎（DM）是特发性炎性肌病最广为人知的亚型。DM肌肉病理学的特征包括微血管病变、炎性浸润和束周萎缩。最近的研究发现揭示了髓过氧化物酶（MPO）在多种疾病状态下通过引起氧化损伤和调节异常免疫而产生的致病作用。在本研究中，我们旨在探讨MPO在DM发病机制中的作用。
分别使用实时定量PCR和亚硫酸氢盐焦磷酸测序验证外周血单个核细胞（PBMC）中MPO的mRNA表达和DNA甲基化。采用酶联免疫吸附测定法检测血浆MPO水平，并分析其与临床特征的关系。通过免疫荧光检测MPO在肌肉中的表达和分布。使用纯化的人天然MPO蛋白刺激人真皮微血管内皮细胞（HDMECs）和骨骼肌肌管。然后观察HDMECs的细胞活力、管形成能力、通透性、黏附分子表达以及肌管中的萎缩和程序性细胞死亡途径。
DM患者中MPO基因甲基化降低，而mRNA表达和血浆水平升高。DM患者的血浆MPO与血清肌酸激酶（CK）呈正相关。在DM肌肉活检中，MPO主要分布在肌内膜毛细血管周围和束周萎缩区域，并与CD4、CD8 T细胞和CD19 B细胞共定位。MPO不仅可以影响HDMECs的细胞活力、管形成能力、通透性和黏附分子（包括细胞间黏附分子1、血管细胞黏附分子1和E选择素）的表达，还可以导致肌管萎缩。
我们的研究首次揭示，MPO在促进DM患者的炎性浸润和诱导肌肉损伤中起重要作用。MPO可能是DM肌肉受累的潜在生物标志物，针对MPO的药物在DM治疗中可能具有前景。
