DataSheet_1_Involvement of CCL2 and CH25H Genes and TNF signaling pathways in mast cell activation and pathogenesis of chronic spontaneous urticaria.pdf

Chronic spontaneous urticaria (CSU), a mast cell-driven disease, substantially affects the quality of life. While genetics affect CSU susceptibility and severity, the specific genetic factors associated with mast cell activation in CSU remain elusive. We aimed to identify key genetic factors and investigate their roles in CSU pathogenesis. Two gene expression datasets from the Gene Expression Omnibus were merged and validated using principal component analysis and boxplots. The merged dataset was subjected to limma and weighted gene co-expression network analyses. Genes whose expression correlated highly with CSU were identified and analyzed using Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. As GSEA, GO, and KEGG analyses highlighted the importance of chemokine (C-C motif) ligand 2 (CCL2) and cholesterol 25-hydroxylase (CH25H) gene and tumor necrosis factor (TNF) signaling pathways in CSU; the three corresponding genes were knocked down in human mast cell line-1 (HMC-1), followed by incubation with thrombin to mimic CSU pathogenesis. CCL2, CH25H, and TNF knockdown reduced excitability and cytokine production in HMC-1. Our findings suggest that genes involved in the CCL2, CH25H, and TNF pathways play crucial roles in CSU pathogenesis, providing insights into potential therapeutic targets for CSU treatment.

慢性自发性荨麻疹（CSU），一种以肥大细胞为驱动力的疾病，显著影响了患者的生活质量。虽然遗传因素影响了CSU的易感性和严重程度，但与CSU中肥大细胞激活相关的特定遗传因素仍难以寻觅。本研究旨在识别关键遗传因素并探讨其在CSU发病机制中的作用。通过主成分分析和箱线图验证，将来自基因表达综合数据库的两个基因表达数据集进行了合并。合并后的数据集经limma和加权基因共表达网络分析处理。鉴定出与CSU高度相关的基因，并利用基因集富集分析（GSEA）、基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析进行了分析。GSEA、GO和KEGG分析突出了趋化因子（C-C基序）配体2（CCL2）和胆固醇25-羟化酶（CH25H）基因以及肿瘤坏死因子（TNF）信号通路在CSU中的重要性；随后，在人类肥大细胞系-1（HMC-1）中敲低这三种基因，并通过与凝血酶孵育来模拟CSU的发病机制。CCL2、CH25H和TNF的敲低降低了HMC-1的兴奋性和细胞因子产生。我们的研究结果提示，参与CCL2、CH25H和TNF途径的基因在CSU发病机制中起着至关重要的作用，为CSU的治疗提供了潜在的靶点。