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.

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

“…With regard to the distribution of ionocytes, direct whole mount tissue analysis of dissected large and small airways identified the presence of CFTR-rich distal ionocytes in indistinguishable numbers along the proximodistal axis of the human airway tree. Recently, experiments in which ionocytes were genetically ablated in the ferret led to aberrant airway surface physiology mirroring the abnormalities seen in CF 12 while the loss of human ionocytes led to abnormalities of ion transport in vitro 14 . Taken together, this suggests that human ionocytes likely play a role in the pathogenesis of both large and small airways disease in CF patients.…”

“…Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the causal gene whose disruption leads to cystic fibrosis (CF) 6,7 . Indeed, their ablation in a ferret model of CF has recently been shown to result in abnormalities of airway physiology remarkably reminiscent of CF, and their loss in human large airway epithelial cultures disrupts ion transport 12–14 . In contrast, tuft cells and NE cells have roles in environmental sensing and initiating inflammatory responses 7,15 .…”

Cell type-specific regulation of CFTR trafficking—on the verge of progress

“…High levels of CFTR expression in ionocytes would suggest an increase in the volume of ASL due to ionocyte liquid secretion. Nonetheless, Lei and coworkers observed an increase in liquid absorption, and consequently a decrease in ASL volume in ionocyte-rich cultures, while a reduction in ionocyte abundance led to an increased liquid secretion ( Lei et al, 2023 ). A possible explanation for that is the presence of basolateral barttin/Cl − channels in ionocytes.…”

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways

“…It is of interest that CFTR proteins are abundantly expressed in forkhead box I1 (FOXI1)-positive pulmonary ionocytes ( Montoro et al, 2018 ; Plasschaert et al, 2018 ), while airway epithelia of FOXI1-knockout mice display increased ciliary beat frequency and mucus viscosity ( Montoro et al, 2018 ). Lei et al ( Lei et al, 2023 ) demonstrated that apical membrane CFTR Cl − channels collaborate with basolateral membrane barttin/ClC-K Cl − channels in ionocytes for transepithelial Cl − absorption, leading to fluid absorption. Moreover, FOXI1-knockout and CF ferrets both display reduced ASL volume and impaired mucociliary clearance due to ASL abnormalities, including slow fluid absorption but also absent fluid secretion, lack of CFTR-mediated ASL alkalization and increased mucus viscosity ( Yuan et al, 2023 ).…”

“…Moreover, FOXI1-knockout and CF ferrets both display reduced ASL volume and impaired mucociliary clearance due to ASL abnormalities, including slow fluid absorption but also absent fluid secretion, lack of CFTR-mediated ASL alkalization and increased mucus viscosity ( Yuan et al, 2023 ). Therefore, albeit less than about 1% of total epithelial cells in airways ( Montoro et al, 2018 ; Plasschaert et al, 2018 ; Lei et al, 2023 ), ionocytes regulate ASL homeostasis. However, whether the dysfunction of ionocytes contributes to the pathogenesis of CF lung diseases needs to be further explored.…”