CFTR-rich ionocytes mediate chloride absorption across airway epithelia
Lei Lei, … , Paul B. McCray Jr., Ian M. Thornell
Lei Lei, … , Paul B. McCray Jr., Ian M. Thornell
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(20):e171268. https://doi.org/10.1172/JCI171268.
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CFTR-rich ionocytes mediate chloride absorption across airway epithelia

Abstract

The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl– into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl– channels in their basolateral membrane. Disrupting barttin/Cl– channel function impaired liquid absorption, and overexpressing barttin/Cl– channels increased absorption. Together, apical CFTR and basolateral barttin/Cl– channels provide an electrically conductive pathway for Cl– flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption.

Authors

Lei Lei, Soumba Traore, Guillermo S. Romano Ibarra, Philip H. Karp, Tayyab Rehman, David K. Meyerholz, Joseph Zabner, David A. Stoltz, Patrick L. Sinn, Michael J. Welsh, Paul B. McCray Jr., Ian M. Thornell

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Figure 9

At least 1 paracellular and 2 transcellular pathways exist for Cl– movement across airway epithelia.

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At least 1 paracellular and 2 transcellular pathways exist for Cl– movem...
The model depicts physiological Na+ and Cl– flow. The locations of each transporter and channel are based on single-cell RNA sequencing, immunolocalization, and functional data. Ionocyte: The apical CFTR channels (green) and basolateral barttin/Cl– channels (red) permit Cl– movement in either direction in response to the transepithelial electrochemical gradient (green bidirectional arrow). At physiological [Cl–], the electrical gradient (Vt) across airway epithelium — primarily established by ENaC (blue in apical membrane) and the Na-K pump (blue in basolateral membrane) — drives Cl– absorption through the ionocyte (depicted by the asymmetry of the green arrowheads). Secretory cell: Secretory cells import Cl– through basolateral NKCC1 (green transporter) to maintain the intracellular Cl– at a concentration that drives Cl– secretion (green unidirectional arrow) through apical CFTR channels (green). The secretory cells also contain a pathway for Na+ absorption (blue unidirectional arrow) through ENaC (blue in apical membrane) and the Na-K pump (blue in basolateral membrane). Paracellular pathway: The paracellular region around epithelial cells, depicted as an exaggerated opening between epithelial cells, provides a pathway for ion movement driven by the transepithelial electrochemical gradient. The thicker line for Na+ (blue bidirectional arrow) compared with Cl– (green bidirectional arrow) represents the cation selectivity of the paracellular pathway and the dominant arrowhead shows the direction of physiological flow. The influences of ciliated cells and other epithelial cell types on transepithelial Cl– flow remain less characterized and are omitted in the model.