Single‐Cell Transcriptomic Analysis on Multi‐Subtypes of Idiopathic Inflammatory Myopathy Reveals Pathologic Hallmarks Associated With Stromal Stem and Immune Cells in Damaged Skeletal Muscles

Objective This study aims to investigate the pathogenic hallmarks in various subtypes of idiopathic inflammatory myopathies (IIM) using single‐cell transcriptomic approaches. Methods Single‐cell RNA sequencing analysis was conducted on affected skeletal muscle and peripheral blood mononuclear cells from healthy controls (n = 5) and patients with four different IIM subtypes (anti‐Mi2/MDA5/NXP2 dermatomyositis [DM] and anti‐HMGCR immune‐mediated necrotizing myopathy [IMNM]; for each subtype, n = 3–5). Immunohistochemistry and cell cultures were performed to confirm key alterations revealed by the single‐cell analysis. Results Among the 12 cell types, a reduction in type IIa/IIx myofiber cells was observed across more inflammatory IIM subtypes. Type I interferon (IFN‐I) signaling was selectively hyperactivated in DM, whereas it is not obvious in IMNM. Expression of the transcription factor MEF2C appears to be reduced and associated with delayed myofiber genesis and altered muscle function. Developmental trajectory analysis suggested that two clusters of muscle stem and progenitor cells, MuSCs1 and Myoblasts1, were associated with disruptions in muscle regeneration in IIM, with IFN‐I indicated in this aberrant differentiation process. Among immune cells, M1‐like macrophages were suggested to interact with muscle cells via tumor necrosis factor signaling, leading to muscle inflammation. Furthermore, CXCL10 + fibroblasts are likely to recruit the M1‐like macrophages through the CCL19‐CCR7/CCRL2 axis. Moreover, we found that peripheral CD14 + monocytes exhibit high IFN activity and polarize into the M1‐like phenotype after infiltration into skeletal muscle. Conclusion The study provides valuable single‐cell transcriptomic resources for describing pathologic cell atlas across IIM subtypes. We highlighted not only common changes in IIM (ie, expression of MEF2C and IFN‐I) but also outlined distinct characteristics among the four subtypes of IIM. image