The type 2 cytokine-high asthma endotype (T2H) is characterized by IL-13-driven mucus obstruction of the airways. To further investigate this incompletely understood pathobiology, we characterize IL-13 effects on human airway epithelial cell cultures using single-cell RNA sequencing, finding that IL-13 generates a distinctive transcriptional state for each cell type. Specifically, we discover a mucus secretory program induced by IL-13 in all cell types which converts both mucus and defense secretory cells into a metaplastic state with emergent mucin production and secretion, while leading to ER stress and cell death in ciliated cells. The IL-13-remodeled epithelium secretes a pathologic, mucin-imbalanced, and innate immunity-depleted proteome that arrests mucociliary motion. Signatures of IL-13-induced cellular remodeling are mirrored by transcriptional signatures characteristic of the nasal airway epithelium within T2H versus T2-low asthmatic children. Our results reveal the epithelium-wide scope of T2H asthma and present candidate therapeutic targets for restoring normal epithelial function.

2型细胞因子高哮喘内型（T2H）的特征在于IL-13驱动的气道粘液阻塞。为了进一步研究这种不完全了解的病理生物学，我们使用单细胞RNA测序表征IL-13对人气道上皮细胞培养的影响，发现IL-13为每种细胞类型产生了独特的转录状态。具体而言，我们发现了由IL-13诱导的所有细胞类型的黏液分泌程序，该程序将黏液和防御性分泌细胞均转化为具有粘液产生和分泌的生化状态，同时导致纤毛细胞内质网应激和细胞死亡。IL-13重塑的上皮分泌一种病理性，粘蛋白失衡的先天性免疫缺陷蛋白，可阻止粘膜纤毛运动。与T2低度哮喘儿童相比，T2H中鼻气道上皮的转录特征反映了IL-13诱导的细胞重塑的特征。我们的研究结果揭示了T2H哮喘的整个上皮范围，并提出了恢复正常上皮功能的候选治疗靶标。