Identification of STAT3 signaling as a shared pathogenic signature in systemic lupus erythematosus, chronic obstructive pulmonary disease, and asthma

Abstract

While patients with systemic lupus erythematosus (SLE) have a higher risk of developing chronic obstructive pulmonary disease (COPD) and asthma, the underlying mechanisms have yet to be elucidated. To this end, by integrating transcriptomic data obtained from blood specimens for each disorder, this study made an effort to investigate shared pathogenic signatures in these three disorders. After identification of shared differentially expressed genes (DEGs), their protein interactions (PPIs) were mapped using a high confidence threshold (0.7). Construction of the networks led to the identification of STAT3 as the central hub gene. Functional enrichment analysis of the shared PPI network of SLE, COPD, and asthma revealed involvement of the shared DEGs in the activation of innate immunity in conjunction with the dysregulation of adaptive immunity, specifically the differentiation of Th1, Th2, and Th17 cells. Moreover, Gene Ontology (GO) analysis highlighted a substantial imbalance between kinase and phosphatase. These observations suggest the STAT3 signaling pathway not only as a pathogenic link between SLE, COPD, and asthma but also as a potential therapeutic target for patients diagnosed with a combination of these disorders.

Keywords: Asthma; Blood; COPD; Comorbidity; SLE; STAT3.

Fig. 1

Identification of shared DEGs in SLE, COPD, and asthma. (a) Distribution of samples in the integrated SLE dataset before batch-effect correction; (b–c) after batch-effect correction. (d) Distribution of samples in the integrated COPD dataset before batch-effect correction; (e–f) after batch-effect correction. (g) Volcano plots of DEGs in SLE. (h) Volcano plots of DEGs in COPD. (i) Volcano plots of DEGs in asthma. (j) A total of 106 genes were commonly upregulated across SLE, COPD, and asthma. (k) A total of 41 genes were commonly downregulated in SLE, COPD, and asthma.

Fig. 2

Networks shared by SLE, COPD, and asthma. (a) miRNA-mRNA regulatory network of hub genes identified in the PPI network constructed using a medium (0.4) confidence threshold. (b) PPI network constructed using a high (0.7) confidence threshold. Upregulated genes are labeled in red, while downregulated genes are labeled in blue. The size of the nodes is positively correlated with the degree metrics. Transcription factors are shown with a diamond shape and green border.

Fig. 3

GO and KEGG pathway analyses of shared DEGs between SLE, COPD, and asthma. (a) Functional enrichment analysis of upregulated genes. (b) Functional enrichment analysis of downregulated genes.