Department of Respiratory Medicine, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou, China.
J Allergy Clin Immunol. 2022 Jul;150(1):192-203. doi: 10.1016/j.jaci.2021.10.041. Epub 2022 Feb 1.
Circular RNAs (circRNAs) play potentially important roles in various human diseases; however, their roles in the goblet cell metaplasia of asthma remain unknown.
We sought to investigate the potential role and underlying mechanism of circZNF652 in the regulation of allergic airway epithelial remodeling.
The differential expression profiles of circRNAs were analyzed by transcriptome microarray, and the effects and mechanisms underlying circZNF652-mediated goblet cell metaplasia were investigated by quantitative real-time PCR, RNA fluorescence in situ hybridization, Western blot, RNA pull-down, and RNA immunoprecipitation analyses. The roles of circZNF652 and miR-452-5p in allergic airway epithelial remodeling were explored in both the mouse model with allergic airway inflammation and children with asthma.
One hundred sixty circRNAs were differentially expressed in bronchoalveolar lavage fluid of children with asthma versus children with foreign body aspiration, and 52 and 108 of them were significantly upregulated and downregulated, respectively. Among them, circZNF652 was predominantly expressed and robustly upregulated in airway epithelia of both the children with asthma and the mouse model with allergic airway inflammation. circZNF652 promoted the goblet cell metaplasia by functioning as a sponge of miR-452-5p, which released the Janus kinase 2 (JAK2) expression and subsequently activated JAK2/signal transducer and activator of transcription 6 (STAT6) signaling in the allergic airway epithelia. In addition, epithelial splicing regulatory protein 1, a splicing factor, accelerated the biogenesis of circZNF652 by binding to its flanking intron to promote the goblet cell metaplasia in allergic airway epithelial remodeling.
Upregulation of circZNF652 expression in allergic bronchial epithelia contributed to the goblet cell metaplasia by activating the miR-452-5p/JAK2/STAT6 signaling pathway; thus, blockage of circZNF652 or agonism of miR-452-5p provided an alternative approach for the therapeutic intervention of epithelial remodeling in allergic airway inflammation.
环状 RNA（circRNAs）在各种人类疾病中发挥着潜在的重要作用；然而，它们在哮喘杯状细胞化生中的作用尚不清楚。
我们旨在研究 circZNF652 在调节过敏性气道上皮重塑中的潜在作用及其潜在机制。
通过转录组微阵列分析环状 RNA 的差异表达谱，并通过定量实时 PCR、RNA 荧光原位杂交、Western blot、RNA 下拉和 RNA 免疫沉淀分析研究 circZNF652 介导的杯状细胞化生的作用和机制。在过敏性气道炎症的小鼠模型和哮喘儿童中，研究了 circZNF652 和 miR-452-5p 在过敏性气道上皮重塑中的作用。
在哮喘儿童与异物吸入儿童的支气管肺泡灌洗液中，有 160 个 circRNAs 差异表达，其中 52 个和 108 个分别显著上调和下调。其中，circZNF652 在哮喘儿童和过敏性气道炎症小鼠模型的气道上皮中均主要表达并显著上调。circZNF652 通过作为 miR-452-5p 的海绵发挥作用，促进杯状细胞化生，从而释放 Janus 激酶 2（JAK2）的表达，并随后激活过敏性气道上皮中的 JAK2/信号转导和转录激活因子 6（STAT6）信号通路。此外，剪接调节蛋白 1（一种剪接因子）通过结合其侧翼内含子加速 circZNF652 的生物发生，从而促进过敏性气道上皮重塑中的杯状细胞化生。
过敏性支气管上皮中 circZNF652 表达的上调通过激活 miR-452-5p/JAK2/STAT6 信号通路促进杯状细胞化生；因此，阻断 circZNF652 或激动 miR-452-5p 为过敏性气道炎症中上皮重塑的治疗干预提供了一种替代方法。
