IL-13 induces loss of CFTR in ionocytes and reduces airway epithelial fluid absorption
Guillermo S. Romano Ibarra, … , Ian M. Thornell, David A. Stoltz
Guillermo S. Romano Ibarra, … , Ian M. Thornell, David A. Stoltz
Published September 10, 2024
Citation Information: J Clin Invest. 2024;134(21):e181995. https://doi.org/10.1172/JCI181995.
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Research Article Pulmonology

IL-13 induces loss of CFTR in ionocytes and reduces airway epithelial fluid absorption

Abstract

The airway surface liquid (ASL) plays a crucial role in lung defense mechanisms, and its composition and volume are regulated by the airway epithelium. The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in a rare airway epithelial cell type called an ionocyte. Recently, we demonstrated that ionocytes can increase liquid absorption through apical CFTR and basolateral barttin/chloride channels, while airway secretory cells mediate liquid secretion through apical CFTR channels and basolateral NKCC1 transporters. Th2-driven (IL-4/IL-13) airway diseases, such as asthma, cause goblet cell metaplasia, accompanied by increased mucus production and airway secretions. In this study, we investigate the effect of IL-13 on chloride and liquid transport performed by ionocytes. IL-13 treatment of human airway epithelia was associated with reduced epithelial liquid absorption rates and increased ASL volume. Additionally, IL-13 treatment reduced the abundance of CFTR-positive ionocytes and increased the abundance of CFTR-positive secretory cells. Increasing ionocyte abundance attenuated liquid secretion caused by IL-13. Finally, CFTR-positive ionocytes were less common in asthma and chronic obstructive pulmonary disease and were associated with airflow obstruction. Our findings suggest that loss of CFTR in ionocytes contributes to the liquid secretion observed in IL-13–mediated airway diseases.

Authors

Guillermo S. Romano Ibarra, Lei Lei, Wenjie Yu, Andrew L. Thurman, Nicholas D. Gansemer, David K. Meyerholz, Alejandro A. Pezzulo, Paul B. McCray, Ian M. Thornell, David A. Stoltz

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Figure 7

CFTR loss in ionocytes is associated with worsening airflow obstruction in asthmatic subjects.

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CFTR loss in ionocytes is associated with worsening airflow obstruction ...
(A–C) Lung histology sections from deceased human donors stained with CFTR (yellow), barttin (magenta, ionocytes), and β-tubulin (cyan, ciliated cells). Sections were obtained from a control without known lung disease (A) and subjects with a history of asthma (B) and status asthmaticus (C). Scale bar: 15 μm. (D–J) scRNA-Seq and pulmonary function data are from Vieira Braga et al. (42). Data are from 6 asthmatic subjects and 6 age-matched controls. scRNA-Seq data were obtained from tracheal biopsies. The authors’ cluster definitions were preserved for this analysis. (D and E) t-SNE plots with cell type clusters for control and asthmatic subjects. (F) Ionocyte cluster. (G) Relative contributions of cell types per subject (individual symbols) by cell cluster identity. (H) Normalized ionocyte CFTR expression for each subject. Within a subject, individual ionocytes are each represented by a symbol. The percentage of ionocytes with CFTR was evaluated for subjects with more than 3 ionocytes. (I) Percentage of ionocytes with CFTR. Each symbol represents a different subject. (J) The percentage of CFTR-positive ionocytes was plotted versus FEV1% predicted for control and asthmatic subjects. The black line represents a nonlinear best-fit model. Data are shown as mean ± SD. P values were obtained by 2-tailed Mann-Whitney ranking test comparing asthmatic donors with control donors. Asth, asthma; Ctrl, control; FEV1, forced expiratory volume in 1 second. *P < 0.05.