Single-cell transcriptomic analysis on multi-subtypes of idiopathic inflammatory myopathy reveals pathological hallmarks associated with stromal stem and immune cells in damaged skeletal muscles.
basic_science · Level V
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- Record sourced from PubMed, PMID 42007840.
- Also identified by DOI 10.1002/art.70185.
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Abstract
This study aims to investigate the pathogenic hallmarks in various subtypes of idiopathic inflammatory myopathies (IIM) using single-cell transcriptomic approaches. Single-cell RNA-sequencing (scRNA-seq) analysis was conducted on affected skeletal muscle and peripheral blood mononuclear cells (PBMC) from healthy controls (n=5) and patients with four different idiopathic inflammatory myopathy (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. Among the twelve cell types, a reduction in typeIIa/x myofiber cells was observed across more-inflammatory IIM subtypes. IFN-I signaling was selectively hyperactivated in DM, while it is not obvious in IMNM. Expression of the transcription factor MEF2C appears to be reduced, 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, are attributed to disruptions in muscle regeneration in IIM, where IFN-I is indicated this aberrant differentiation process. Among immune cells, M1-like macrophages were suggested to interact with muscle cells via TNF signaling, leading to muscle inflammation. Furthermore, CXCL10<sup>+</sup> fibroblasts are likely to recruit the M1-like macrophages through the CCL19-CCR7/CCRL2 axis. Moreover, we found that peripheral CD14<sup>+</sup> monocytes exhibit high IFN activity and polarize into the M1-like phenotype upon infiltration into skeletal muscle. The study provides valuable single-cell transcriptomic resources for describing pathological cell atlas across IIM subtypes. We highlighted not only common changes in IIM (i.e. expression of MEF2C and IFN-I) but also outlined distinct characteristics among the four subtypes of IIM.