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Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma.

  • Author(s): Jackson, Nathan D;
  • Everman, Jamie L;
  • Chioccioli, Maurizio;
  • Feriani, Luigi;
  • Goldfarbmuren, Katherine C;
  • Sajuthi, Satria P;
  • Rios, Cydney L;
  • Powell, Roger;
  • Armstrong, Michael;
  • Gomez, Joe;
  • Michel, Cole;
  • Eng, Celeste;
  • Oh, Sam S;
  • Rodriguez-Santana, Jose;
  • Cicuta, Pietro;
  • Reisdorph, Nichole;
  • Burchard, Esteban G;
  • Seibold, Max A
  • et al.
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.

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