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IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function
Maya E. Kotas, … , Max A. Seibold, Erin D. Gordon
Maya E. Kotas, … , Max A. Seibold, Erin D. Gordon
Published May 24, 2022
Citation Information: JCI Insight. 2022;7(13):e159832. https://doi.org/10.1172/jci.insight.159832.
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Research Article Inflammation Pulmonology

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

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Abstract

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor–dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

Authors

Maya E. Kotas, Camille M. Moore, Jose G. Gurrola II, Steven D. Pletcher, Andrew N. Goldberg, Raquel Alvarez, Sheyla Yamato, Preston E. Bratcher, Ciaran A. Shaughnessy, Pamela L. Zeitlin, Irene H. Zhang, Yingchun Li, Michael T. Montgomery, Keehoon Lee, Emily K. Cope, Richard M. Locksley, Max A. Seibold, Erin D. Gordon

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Figure 1

Single-cell sequencing reveals expansion and allergic activation of tuft cells in nasal polyps.

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Single-cell sequencing reveals expansion and allergic activation of tuft...
(A) Uniform manifold approximation and projection (UMAP) of scRNA-Seq of epithelial cells from healthy ethmoid sinus (control; n = 4) or nasal polyp (n = 5) (total cells = 116,358) reveals 10 cell types. (B) Expanded view of inset in A showing tuft cells and ionocytes identified by hierarchical subclustering. (C) Expression of tuft cell and ionocyte marker genes in tuft and ionocyte subclusters. (D) Percentage of ionocytes and tuft cells among total epithelial cells in control or polyp. Error bars indicate mean ± SEM. *P < 0.05 by Mann-Whitney t test with correction for multiple comparisons. (E) RNA in situ hybridization for POU2F3 (red) and immunofluorescence for E-cadherin (shown in green) identifies increased numbers of tuft cells (arrow) in nasal polyp epithelium as compared with control ethmoid (representative of 3 samples from 3 patients of each type). Scale bars: 60 μm. (F) Shared tuft cell marker genes (“common markers”) and differentially expressed genes (DEGs) (“polyp tuft markers”) in tuft (dark orange) and nontuft cells (light orange) from control (light purple) and polyp (dark purple) epithelium. Expression of representative (G) common tuft cell marker POU2F3 and polyp tuft markers (H) ALOX5 and (I) PTGS1.

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