Center for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206, USA.
Department of Physics, University of Cambridge, Cambridge, CB2 3AX, UK.
Cell Rep. 2020 Jul 7;32(1):107872. doi: 10.1016/j.celrep.2020.107872.
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 型细胞因子高哮喘表型（T2H）的特征是 IL-13 驱动气道黏液阻塞。为了进一步研究这种尚未完全了解的病理生物学，我们使用单细胞 RNA 测序来描述 IL-13 对人呼吸道上皮细胞培养物的影响，发现 IL-13 为每种细胞类型生成独特的转录状态。具体来说，我们发现 IL-13 在所有细胞类型中诱导了一个黏液分泌程序，将黏液和防御性分泌细胞转化为具有新兴黏蛋白产生和分泌的化生状态，而导致纤毛细胞内质网应激和细胞死亡。IL-13 重塑的上皮组织分泌一种病理性的、黏液失衡的、先天免疫耗竭的蛋白质组，阻止黏液纤毛运动。IL-13 诱导的细胞重塑特征与 T2H 与 T2-低哮喘儿童的鼻气道上皮的转录特征相吻合。我们的结果揭示了 T2H 哮喘的上皮广泛范围，并提出了恢复正常上皮功能的候选治疗靶点。
