Xuan Lingling, Ren Lulu, Zhang Wen, An Zhuoling
Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China.
J Inflamm Res. 2025 Sep 9;18:12379-12400. doi: 10.2147/JIR.S527640. eCollection 2025.
Corticosteroid resistance in asthma, marked by reduced glucocorticoid response, is significantly influenced by cigarette smoke (CS). We sought to explore potential novel biomarkers and therapeutic targets associated with CS-induced corticosteroid resistance in asthma.
GSE230048 (related to corticosteroid resistance) and GSE13896 (from CS-exposed macrophages) were obtained from GEO. Initially, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to discover key genes involved in corticosteroid resistance in asthma. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic accuracy of these markers. CIBERSORT was applied to clarify immune cell infiltration. Expression of the key biomarker was validated in asthma patients and asthma murine models.
Five overlapping genes upregulated in corticosteroid-resistant asthma patients and smokers' alveolar macrophages were identified. Subsequently, using WGCNA, the most relevant modules were identified and intersected with differentially expressed genes. Tensin 1 (TNS1), ATP-binding cassette subfamily C member 4 (ABCC4), and TNF receptor superfamily member 21 (TNFRSF21) were identified as critical biomarkers for corticosteroid resistance in asthma. ROC analysis showed an AUC of 0.718 for the three-marker combination. Single-cell RNA sequencing confirmed their expression in macrophages from asthmatic patients. Elevated levels of TNS1, ABCC4, TNFRSF21, and M2 macrophage markers (CD301 and CD206) were observed in CS-exposed murine lung tissues and CS condensate-treated Raw264.7 cells. TNS1 knockdown significantly reduced CD301 and CD206 expression, suggesting its role in promoting macrophage M2 polarization.
In conclusion, we identified three hub genes (TNS1, ABCC4, and TNFRSF21) associated with CS-induced corticosteroid resistance in asthma. Additionally, TNS1 may be involved in CS-induced corticosteroid resistance in asthma by promoting macrophage M2 polarization.
哮喘中的糖皮质激素抵抗以糖皮质激素反应降低为特征，受香烟烟雾（CS）的显著影响。我们试图探索与CS诱导的哮喘糖皮质激素抵抗相关的潜在新型生物标志物和治疗靶点。
从基因表达综合数据库（GEO）获取GSE230048（与糖皮质激素抵抗相关）和GSE13896（来自暴露于CS的巨噬细胞）。最初，我们进行差异基因表达分析和加权基因共表达网络分析（WGCNA）以发现参与哮喘糖皮质激素抵抗的关键基因。进行基因本体论（GO）术语和京都基因与基因组百科全书（KEGG）通路富集分析。采用受试者工作特征（ROC）分析评估这些标志物的诊断准确性。应用CIBERSORT来阐明免疫细胞浸润情况。在哮喘患者和哮喘小鼠模型中验证关键生物标志物的表达。
在糖皮质激素抵抗的哮喘患者和吸烟者的肺泡巨噬细胞中鉴定出5个上调的重叠基因。随后，使用WGCNA鉴定出最相关的模块，并与差异表达基因进行交叉分析。张力蛋白1（TNS1）、ATP结合盒亚家族C成员4（ABCC4）和肿瘤坏死因子受体超家族成员21（TNFRSF21）被鉴定为哮喘糖皮质激素抵抗的关键生物标志物。ROC分析显示三标志物组合的曲线下面积（AUC）为0.718。单细胞RNA测序证实它们在哮喘患者巨噬细胞中的表达。在暴露于CS的小鼠肺组织和经CS冷凝物处理的Raw264.7细胞中观察到TNS1、ABCC4、TNFRSF21和M2巨噬细胞标志物（CD301和CD206）水平升高。TNS1基因敲低显著降低CD301和CD206表达，表明其在促进巨噬细胞M2极化中的作用。
总之，我们鉴定出与CS诱导的哮喘糖皮质激素抵抗相关的3个枢纽基因（TNS1、ABCC4和TNFRSF21）。此外，TNS1可能通过促进巨噬细胞M2极化参与CS诱导的哮喘糖皮质激素抵抗。
