Transcriptome analysis identifies IL24 as an autophagy modulator in PM2.5 caused lung dysfunction
Transcriptome analysis identifies IL24 as an autophagy modulator in PM2.5 caused lung dysfunction
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DOI：
10.1016/j.ecoenv.2022.114039
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发表时间：
2022-08-30
影响因子：
6.8
通讯作者：
Li, Guoping
中科院分区：
文献类型：
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作者：
Liu, Yao;He, Xiang;Li, Guoping
背景：有证据表明，暴露在PM2.5中会增加呼吸系统疾病的住院率和死亡率。然而，与PM2.5引起的肺功能障碍相关的潜在生物标志物和靶点还没有完全被发现。方法：应用基因本体论(GO)、京都基因与基因组百科全书(KEGG)和标记富集法对经PM2.5处理的BEAS-2B细胞的RNA-SEQ数据进行分析。基因集浓缩分析(GSEA)用于鉴定与自噬相关的生物学过程。从基因表达总表(GEO)数据库下载三个基因表达谱数据集(GSE158954、GSE155616和GSE182199)以确定潜在靶点。建立PM2.5(2.5)暴露小鼠模型。采用实时荧光定量聚合酶链式反应、siRNA转染、免疫印迹、免疫荧光和病理染色等方法进行体内和体外研究。结果：GO、KEGG和基于RNA-SEQ数据的HARMARK富集法显示差异表达基因(DEG)与溶酶体样自噬和巨型自噬相关。GSEA分析显示，与对照组相比，PM2.5与自噬相关的生物学过程呈正相关。在PM(2.5)暴露后，我们的数据以及这三个数据集(GSE158954、GSE155616和GSE182199)中IL24的维恩图被上调。与分析一致的是，PM2.5激活自噬在体内和体外都得到了验证。在暴露于PM2.5(2.5)的小鼠中，观察到肺的病理变化，包括呼吸道炎症和粘液分泌。关键基因IL24的mRNA和蛋白水平显著升高。此外，自噬抑制剂巴菲罗星A1可抑制PM2.5诱导的自噬，减轻PM2.5所致的肺损伤。此外，IL24的下调降低了自噬活性。同时，IL24受mTOR信号调节。结论：综上所述，我们发现在PM2.5暴露过程中IL24和自噬之间存在潜在的关系。IL24可能是PM2.5通过调节自噬导致肺功能障碍的一种新的潜在生物标志物或治疗靶点。
Background: Evidence suggests that exposure to PM2.5 increased hospitalization and mortality rates of respiratory diseases. However, the potential biomarkers and targets associated with PM2.5-induced lung dysfunction are not fully discovered. Methods: Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and HALLMARK enrichment analysis of the RNA-seq data (Beas-2B cells treated with PM2.5) were applied. Gene set enrichment analysis (GSEA) was performed to identify the biological processes correlated with autophagy. Three gene expression profile datasets (GSE158954, GSE155616 and GSE182199) were downloaded from the Gene Expression Omnibus (GEO) database to identify the potential targets. PM2.5(2.5)-exposed mice were constructed. Real-time qPCR, siRNA transfection, western blot, immunofluorescence, and pathological staining were applied for validation both in vitro and in vivo studies. Results: GO, KEGG and HALLMARK enrichment based on RNA-seq data showed that the differentially expressed genes (DEGs) were associated with autophagy like lysosome and macroautophagy. GSEA analysis revealed that PM2.5 was positively correlated with autophagy-related biological processes compared with control group. Venn diagrams identified IL24 was upregulated in our data as well as in these three datasets (GSE158954, GSE155616 and GSE182199) after PM(2.5 )exposure. Consistent with the analysis, activation of autophagy by PM2.5 was validated in vivo and in vitro. In PM2.5(2.5)-exposed mice, lung pathological changes were observed, including airway inflammation and mucus secretion. The mRNA and protein levels of the key gene, IL24, were significantly increased. Moreover, Bafilomycin A1, the inhibitor of autophagy, inhibited the autophagy and ameliorated lung injury induced by PM2.5. Furthermore, downregulation of IL24 decreased autophagy activity. Meanwhile, IL24 was regulated by mTOR signaling. Conclusions: In summary, we discovered a potential relationship between IL24 and autophagy during PM2.5 exposure. IL24 might be a novel potential biomarker or therapeutic target in PM2.5 caused lung dysfunction through regulation of autophagy.