Transcriptomic analyses identify TMPRSS4 as a shared biomarker in asthma and atopic dermatitis

Asthma and atopic dermatitis (AD) are common chronic inflammatory diseases that often co-occur, but the underlying shared biological mechanisms remain elusive. In this study, we performed WGCNA analyses on GSE6012 and GSE67472 datasets and identified 24 genes associated with both AD and asthma. We observed that transmembrane protease serine 4 (TMPRSS4) showed significant upregulation in both asthma and AD patients across two independent datasets (GSE6012/GSE67472) using Wilcoxon testing with high receiver operating characteristic (ROC) curve performance, suggesting it may serve as a common biological marker for the co-occurrence of asthma and AD. To elucidate the biological role of TMPRSS4, we first validated its expression profile using Reverse transcription quantitative PCR (RT-qPCR), western blotting and immunofluorescence in HaCaT and BEAS-2B cell models. Subsequently, we performed TMPRSS4 knockout in these two cell lines and conducted RNA-Seq analysis, which revealed that TMPRSS4 might be involved in signal transduction and immune response pathways. Further investigation into the closely related signal transducer and activator of transcription 3 (STAT3) signaling pathway showed that knockout of TMPRSS4 led to increased phosphorylation at the Ser727 site and decreased phosphorylation at the Tyr705 site of STAT3. Moreover, TMPRSS4-/- cells exhibited increased endoplasmic reticulum (ER)-mitochondrion contacts. These findings suggest that TMPRSS4 may exert its function through regulating ER-mitochondrial function. Our study provides novel insights into the role of TMPRSS4 in the pathogenesis of asthma and AD co-occurrence and highlights its potential as a therapeutic target.