Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea

OBJECTIVE: Rosacea is a chronic inflammatory skin disease with high morbidity. Previous studies have described the contribution of skin barrier dysfunction (SBD) in the progression of rosacea, but the specific mechanism remains unclear. In this study, we aim to investigate the key genes that may involve SBD-mediated rosacea aggravation. METHODS: In this study, we evaluated the SBD patterns of rosacea based on the expression of 23 skin barrier-related genes (SBRGs) using a consensus clustering analysis, and revealed the SBD-mediated immune cells infiltration in rosacea using GSE65914 dataset. The key genes associated with SBD and rosacea progression were identified using WGCNA analysis and then verified in rosacea mice model. RESULTS: Two distinct SBD patterns (moderate- and high-SBD patterns) were determined in rosacea. GO, KEGG and GSEA analysis revealed the differently immune-related signal pathways between two SBD patterns in rosacea. The XCell immune cell assays showed that the increased immune infiltration with SBD. Subsequently, the WGCNA analysis identified STAT3 as the hub gene related to rosacea and SBD, and correlation analysis revealed that STAT3 could contribute to the progression of rosacea partly by dysregulating immune infiltration via activating the cytokine/chemokines signal. Finally, the up-regulated STAT3 was verified in the epidermis of rosacea tissues and correlated with SBRGs expression using IHC and epidermal transcriptome data of rosacea. The vivo experiment showed that tape stripping-induced SBD evidently induced the expression of STAT3 and increased CD4(+) T cell infiltration in LL37-induced rosacea-like skin lesion in mice. CONCLUSION: In conclusion, our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes.