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

Abstract

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.

Pyroptosis‐related gene signature elicits immune response in rosacea

“…Memory T cells and B cells could quickly response to the triggers stimulated again 51,52 . Previous studies have found that CD4 + memory T‐cell infiltrations were significantly elevated in rosacea compared with healthy individuals 26 . This suggested that the increased memory T cells may contribute to a faster and more serious inflammatory response when being triggered by a series of pathogenesis conditions mentioned above.…”

“…51,52 Previous studies have found that CD4 + memory T-cell infiltrations were significantly elevated in rosacea compared with healthy individuals. 26 This suggested that the increased memory T cells may contribute to a faster and more serious inflammatory response when being triggered by a series of pathogenesis conditions mentioned above. Macrophages were diffusely distributed in rosacea, which especially located in granulomatous areas and interfollicular areas of PPR, 47,53 and inflammatory reaction in rosacea could be alleviated by carvedilol through TLR2/KLK5/cathelicidin pathway in macrophages.…”

“…27,41 This may trigger a series of cellular pyroptosis Progress in rosacea research over the past two decades has implicated the vital role of immune disorder, reflected with various abnormal immune cell infiltrations during the pathogenesis of rosacea, such as neutrophils, CD4 + T cells, B cells, macrophages and macrophages M1. 13,14,26,42 Triggered by the pathogenetic conditions (e.g., microbes, UV, spicy food and smoking), 43,44 chemokine and cytokine response initialled contributing to immune infiltration in the aggravation of rosacea. 28 Detailly, a large number of neutrophils were recruited by the bacterium proteins produced from Demodex mites in rosacea, which could promote the cytokine production abilities, migration and degranulation of neutrophils.…”

Cytokine profile of the epidermis is region specific and may determine the characteristics of inflammation

“…12,13 Barrier damage and changes in the production of epimmunome molecules (loss of sfT-SLP, high AMP level) are also suggested as drivers of papulopustular rosacea (PPR), which is localized to sebaceous SGR skin area. 4,[14][15][16][17] On the other hand, psoriasis, initiated rather by autoantigen presentation instead of outer epidermal/barrier challenges from the outside world, can be considered an inside-out dermatosis. 18 The objective of this study was (i) to determine the relative expression of cytokine-type epimmunome mediators in the three healthy skin regions, (ii) to calculate their absolute cytokine profiles, (iii) to better understand the function of the epimmunome profiles in the distinct regions by a literature search and (iv) to assess the most prominent epimmunome changes in outer epidermal challengedriven outside-in and inside-out skin diseases (AD, PPR and psoriasis respectively).…”

“…One such disease is atopic dermatitis (AD) which is initiated by barrier dysfunction followed by high IL‐25 and IL‐33 production and typically appears on dry GP skin region 12,13 . Barrier damage and changes in the production of epimmunome molecules (loss of sfTSLP, high AMP level) are also suggested as drivers of papulopustular rosacea (PPR), which is localized to sebaceous SGR skin area 4,14–17 . On the other hand, psoriasis, initiated rather by autoantigen presentation instead of outer epidermal/barrier challenges from the outside world, can be considered an inside‐out dermatosis 18 …”