Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma
Nathan D. Jackson, Jamie L. Everman, Maurizio Chioccioli, Luigi Feriani, Katherine C. Goldfarbmuren, Satria P. Sajuthi, Cydney Rios, Roger Powell, Michael Armstrong, Joe Gomez, Cole R. Michel, Celeste Eng, Sam S. Oh, José Rodríguez‐Santana, Pietro Cicuta, Nichole Reisdorph, Esteban G. Burchard, Max A. Seibold
Abstract
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.