Abstract
Dermatomyositis (DM), an inflammatory disorder, is often associated with interstitial lung disease (ILD). However, the underlying mechanism remains unclear. Our study performed RNA sequencing (RNA-seq) and integrative bioinformatics analysis of differentially expressed genes (DEGs) in patients with dermatomyositis-associated interstitial lung disease (DM-ILD) and healthy controls. A total of 2,018 DEGs were identified between DM-ILD and healthy blood samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that DEGs were mainly involved in immune- and inflammatory-related biological processes and pathways. Disease ontology (DO) enrichment analysis identified 35 candidate key genes involved in both skin and lung diseases. Meanwhile, a total of 886 differentially expressed alternative splicing (AS) events were found between DM-ILD and healthy blood samples. After overlapping DEGs with differential AS genes, the plasminogen activator and urokinase receptor (PLAUR) involved in immune-related biological processes and complement and coagulation cascades was screened and identified as the most important gene associated with DM-ILD. The protein–protein interaction (PPI) network revealed that PLAUR had interactions with multiple candidate key genes. Moreover, we observed that there were significantly more neutrophils and less naive B cells in DM-ILD samples than in healthy samples. And the expression of PLAUR was significantly positively correlated with the abundance of neutrophils. Significant higher abundance of PLAUR in DM-ILD patients than healthy controls was validated by RT-qPCR. In conclusion, we identified PLAUR as an important player in regulating DM-ILD by neutrophil-associated immune response. These findings enrich our understanding, which may benefit DM-ILD patients.
Highlights
Dermatomyositis (DM) is an autoimmune disease characterized by the inflammation of skeletal muscles and skin lesions
Statistical results of raw data and clean data are shown in Supplementary Material S3, proving that clean data can be used for following mapping
We found that differentially expressed genes (DEGs) were mainly enriched into immune and inflammation biological processes, such as neutrophil activation, neutrophil-mediated immunity, neutrophil degranulation, neutrophil activation involved in immune response, leukocyte migration, humoral immune response, leukocyte chemotaxis and response to the molecule of bacterial origin (Figure 2A), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, such as cytokine–cytokine receptor interaction, ECM-receptor interaction, IL-17 signaling pathway, NF-kappa B signaling pathway, PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, complement and coagulation cascades, and JAK-STAT signaling pathway (Figure 2B)
Summary
Dermatomyositis (DM) is an autoimmune disease characterized by the inflammation of skeletal muscles and skin lesions. Patients with ILD may have minimal, absent, or late-onset myositis or skin lesions (Friedman et al, 1996; Tillie-Leblond et al, 2008). MHC polymorphisms (Miller et al, 2013), epigenetic modification, and miRNA activity (Gao et al, 2018; Gao et al, 2019), which are important regulators of gene expression, have been reported to play a role in DM pathogenesis. For these reasons, the identification of key molecules involved in DM-ILD is highly required for improving the clinical outcome, and the role of their transcriptional regulations in the etiology of DM has great significance for investigation
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