哮喘是最常见的慢性炎症之一,但仍缺乏有效的诊断标志物和治疗靶点。为了获得更深入的见解,我们使用三种机器学习算法在基因表达综合数据库中全面分析了哮喘患者和健康受试者气道上皮样本的微阵列数据集.我们的调查发现了一个关键基因,STEAP4.发现STEAP4在过敏性哮喘患者中的表达降低。此外,研究发现,它与疾病的严重程度呈负相关,随后在哮喘小鼠中得到了验证。STEAP4的ROC分析显示AUC值大于0.75。STEAP4的功能富集分析表明与IL-17,类固醇激素的生物合成,和铁凋亡信号通路。随后,使用从气道上皮细胞获得的单细胞RNA测序数据进行细胞间通讯分析.结果显示,与具有高STEAP4表达的样品相比,表现出低水平STEAP4表达的样品具有更丰富的MIF信号传导途径。通过体外和体内实验,我们进一步证实STEAP4在气道上皮细胞中的过度表达导致MIF的表达降低,这反过来又导致细胞因子IL-33,IL-25和IL-4的水平降低;相反,当STEAP4在气道上皮细胞中被抑制时,MIF表达上调,导致细胞因子IL-33、IL-25和IL-4的水平升高。这些发现表明,气道上皮中的STEAP4通过抑制MIF信号通路减少过敏性哮喘Th2型炎症反应。
Asthma comprises one of the most common chronic inflammatory conditions, yet still lacks effective diagnostic markers and treatment targets. To gain deeper insights, we comprehensively analyzed microarray datasets of airway epithelial samples from asthmatic patients and healthy subjects in the Gene Expression Omnibus database using three machine learning algorithms. Our investigation identified a pivotal gene,
STEAP4. The expression of
STEAP4 in patients with allergic asthma was found to be reduced. Furthermore, it was found to negatively correlate with the severity of the disease and was subsequently validated in asthmatic mice in this study. A ROC analysis of
STEAP4 showed the AUC value was greater than 0.75. Functional enrichment analysis of STEAP4 indicated a strong correlation with IL-17, steroid hormone biosynthesis, and ferroptosis signaling pathways. Subsequently, intercellular communication analysis was performed using single-cell RNA sequencing data obtained from airway epithelial cells. The results revealed that samples exhibiting low levels of
STEAP4 expression had a richer MIF signaling pathway in comparison to samples with high
STEAP4 expression. Through both in vitro and in vivo experiments, we further confirmed the overexpression of STEAP4 in airway epithelial cells resulted in decreased expression of MIF, which in turn caused a decrease in the levels of the cytokines IL-33, IL-25, and IL-4; In contrast, when the STEAP4 was suppressed in airway epithelial cells, there was an upregulation of MIF expression, resulting in elevated levels of the cytokines IL-33, IL-25, and IL-4. These findings suggest that STEAP4 in the airway epithelium reduces allergic asthma Th2-type inflammatory reactions by inhibiting the MIF signaling pathway.