Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
These authors contributed equally to this work.
Eur Respir J. 2023 Sep 28;62(3). doi: 10.1183/13993003.02210-2022. Print 2023 Sep.
Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33) is thought to limit its activity. We investigated whether IL-33 has functional activities that are independent of ST2 in the airway epithelium.
epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33 and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis.
We demonstrate that IL-33 forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling . IL-33 increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33 pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33 were enriched in airway epithelia from patients with severe COPD.
Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.
上皮损伤、修复和重塑是包括慢性阻塞性肺疾病（COPD）在内的慢性气道疾病的关键特征。受损气道上皮细胞释放的白细胞介素（IL）-33 引起炎症，其受体为血清刺激因子-2（ST2）。IL-33 被氧化为非 ST2 结合形式（IL-33）被认为限制了其活性。我们研究了 IL-33 在气道上皮细胞中是否具有独立于 ST2 的功能活性。
使用上皮损伤测定法和健康及 COPD 上皮的三维、气液界面（ALI）细胞培养模型来阐明 IL-33 的功能作用。使用 bulk 和单细胞 RNA 测序分析评估 IL-33 处理的健康 ALI 培养物和 IL-33 中和抗体处理的 COPD ALI 培养物中发生的转录组变化。
我们证明 IL-33 与气道上皮细胞上表达的晚期糖基化终产物受体（RAGE）和表皮生长因子受体（EGFR）形成复合物。这种替代的、不依赖于 ST2 的途径的激活会损害上皮伤口闭合并诱导气道上皮重塑。IL-33 增加了产生粘液的细胞的比例并降低了上皮防御功能，模拟了 COPD 的致病特征。在 COPD 上皮细胞中中和 IL-33 途径可逆转这些有害特征。定义 IL-33 致病作用的基因特征在严重 COPD 患者的气道上皮中富集。
我们的研究首次揭示了 IL-33、RAGE 和 EGFR 一起在气道上皮细胞中通过不依赖于 ST2 的途径发挥作用，并控制 COPD 中异常的上皮重塑和黏液阻塞特征。
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