School of Medicine, Southwest Jiaotong University, Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610031, China.
School of Medicine, Southwest Jiaotong University, Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China.
Ecotoxicol Environ Saf. 2022 Oct 1;244:114039. doi: 10.1016/j.ecoenv.2022.114039. Epub 2022 Aug 30.
Evidence suggests that exposure to PM increased hospitalization and mortality rates of respiratory diseases. However, the potential biomarkers and targets associated with PM-induced lung dysfunction are not fully discovered.
Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and HALLMARK enrichment analysis of the RNA-seq data (Beas-2B cells treated with PM) 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. PM-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.
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 PM 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 exposure. Consistent with the analysis, activation of autophagy by PM was validated in vivo and in vitro. In PM-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.
In summary, we discovered a potential relationship between IL24 and autophagy during PM exposure. IL24 might be a novel potential biomarker or therapeutic target in PM caused lung dysfunction through regulation of autophagy.
有证据表明，PM 的暴露会增加呼吸道疾病的住院率和死亡率。然而，与 PM 诱导的肺功能障碍相关的潜在生物标志物和靶点尚未完全发现。
对 PM（Beas-2B 细胞）处理后的 RNA-seq 数据进行基因本体论（GO）、京都基因与基因组百科全书（KEGG）和 HALLMARK 富集分析。进行基因集富集分析（GSEA）以鉴定与自噬相关的生物学过程。从基因表达综合数据库（GEO）下载了三个基因表达谱数据集（GSE158954、GSE155616 和 GSE182199），以鉴定潜在的靶标。构建 PM 暴露的小鼠模型。在体外和体内研究中，应用实时 qPCR、siRNA 转染、western blot、免疫荧光和病理染色进行验证。
基于 RNA-seq 数据的 GO、KEGG 和 HALLMARK 富集分析表明，差异表达基因（DEGs）与自噬相关，如溶酶体和巨自噬。GSEA 分析表明，与对照组相比，PM 与自噬相关的生物学过程呈正相关。Venn 图显示，在我们的数据以及这三个数据集（GSE158954、GSE155616 和 GSE182199）中，IL24 在 PM 暴露后上调。与分析一致，PM 在体内和体外均能激活自噬。在 PM 暴露的小鼠中，观察到肺部病理变化，包括气道炎症和粘液分泌。关键基因 IL24 的 mRNA 和蛋白水平显著增加。此外，自噬抑制剂 Bafilomycin A1 抑制了 PM2.5 诱导的自噬和肺损伤。此外，IL24 的下调降低了自噬活性。同时，IL24 受 mTOR 信号通路调节。
综上所述，我们在 PM 暴露过程中发现了 IL24 与自噬之间的潜在关系。IL24 可能是 PM 引起的肺功能障碍的一种新的潜在生物标志物或治疗靶点，通过调节自噬发挥作用。
