Puzzle resolved: CFTR mediates chloride homeostasis by segregating absorption and secretion to different cell types
Burkhard Tümmler
Burkhard Tümmler
Published October 16, 2023
Citation Information: J Clin Invest. 2023;133(20):e174667. https://doi.org/10.1172/JCI174667.
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Commentary

Puzzle resolved: CFTR mediates chloride homeostasis by segregating absorption and secretion to different cell types

Abstract

In the lungs, the cystic fibrosis transmembrane conductance regulator (CFTR) regulates ion transport in surface-airway epithelia and submucosal glands, thus determining airway surface liquid (ASL) volume and mucus hydration. In this issue of the JCI, Lei Lei and colleagues report that the CFTR-rich and barttin/Cl– channel–expressing ionocytes mediate chloride absorption across airway epithelia, whereas the more abundant basal cells and secretory cells mediate chloride secretion. Thus, CFTR-mediated secretion and absorption of chloride ions in the lung are segregated by cell type, which has implications for future molecular therapies for cystic fibrosis lung disease.

Authors

Burkhard Tümmler

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Figure 1

CFTR mediates chloride movement in ionocytes and secretory cells of human lungs.

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CFTR mediates chloride movement in ionocytes and secretory cells of huma...
The airway epithelium contains few ionocytes as a percentage of total cells, but this cell type has the highest expression of CFTR in airway cells. In comparison, secretory cells are the dominant cell type that expresses CFTR in the surface epithelium. At physiological chloride concentrations, the transepithelial electrochemical gradient drives chloride absorption through the ionocyte. Apical CFTR channels and basolateral barttin/Cl– channels mediate the flow of chloride ions. The electrical gradient across the airway epithelium is generated by apical ENaCs, and the basolateral Na-K pump drives chloride absorption. These characteristics allow pulmonary ionocytes to absorb liquid from the apical ASL. In contrast, secretory cells import chloride ions via basolateral NKCC1 and secrete chloride through apical CFTR channels. In these cells, apical ENaC and the Na-K pump share a pathway for absorbing sodium. Notably, CFTR serves opposite functions in different cell types. Figure adapted from Lei et al. (9).