METHODS: Microarray datasets of CSU were obtained from Gene Expression Omnibus database. Differentially expressed genes between skin lesions of CSU and normal controls (LNS-DEGs) were identified, and the enrichment analyses of LNS-DEGs were performed. Hub genes of LNS-DEGs were selected by protein-protein interaction analysis. The co-expression and transcriptional regulatory networks of hub genes were conducted using GeneMANIA and TRRUST database, respectively. CIBERSORT was utilized for immune cell infiltration analysis. Experimental validation was performed by β-hexosaminidase release examination and passive cutaneous anaphylaxis (PCA) mouse model.
RESULTS: A total of 247 LNS-DEGs were identified, which were enriched in cell migration, cell chemotaxis, and inflammatory pathways such as TNF and interleukin (IL) -17 signaling pathway. Among LNS-DEGs, seven upregulated (PTGS2, CCL2, IL1B, CXCL1, IL6, VCAM1, ICAM1) and one downregulated hub gene (PECAM1) were selected. Immune infiltration analysis identified eight different immune cells, such as activated/resting mast cells and neutrophils. Furthermore, PTGS2, encoding cyclooxygenase 2 (COX2), was selected for further validation. COX2 inhibitor, celecoxib, significantly inhibited mast cell degranulation, and reduced vascular permeability and inflammatory cytokine expression in PCA mouse model.
CONCLUSIONS: PTGS2 may be a potential regulator of immunity and inflammation in CSU. Targeting PTGS2 is a new perspective for CSU treatment.
方法:从基因表达综合数据库获得CSU的微阵列数据集。鉴定CSU皮损与正常对照(LNS-DEGs)的差异表达基因,并进行了LNS-DEGs的富集分析。通过蛋白质-蛋白质相互作用分析选择LNS-DEGs的Hub基因。使用GeneMANIA和TRRUST数据库进行了hub基因的共表达和转录调控网络,分别。CIBERSORT用于免疫细胞浸润分析。通过β-己糖胺酶释放检查和被动皮肤过敏反应(PCA)小鼠模型进行实验验证。
结果:总共确定了247个LNS-DEG,它们富含细胞迁移,细胞趋化性,和炎症途径如TNF和白细胞介素(IL)-17信号通路。在LNS-DEG中,七个上调(PTGS2,CCL2,IL1B,选择CXCL1,IL6,VCAM1,ICAM1)和一个下调的hub基因(PECAM1)。免疫浸润分析确定了八种不同的免疫细胞,如激活/静止的肥大细胞和中性粒细胞。此外,PTGS2,编码环氧合酶2(COX2),选择进行进一步验证。COX2抑制剂,塞来昔布,显著抑制肥大细胞脱颗粒,并降低PCA小鼠模型的血管通透性和炎性细胞因子的表达。
结论:PTGS2可能是CSU免疫和炎症的潜在调节因子。靶向PTGS2是CSU治疗的新视角。