WS09.03SLC26A9-mediated chloride transport is important for mucociliary clearance by healthy and cystic fibrosis airway epithelium

Abstract

Genetic studies identified the solute carrier family 26 member 9 (SLC26A9) chloride transporter as a modifier of lung function in health and in cystic fibrosis (CF). Further, genetic deletion of SLC26A9 in mice showed that SLC26A9–mediated chloride secretion is required to prevent mucus obstruction in type 2 airway inflammation. These data suggest that SLC26A9 is a promising therapeutic target in CF and potentially in other muco-obstructive lung diseases, however, its role in coordinated ion transport and mucociliary clearance in the human airways is not well understood. We generated human nasal epithelial (HNE) cultures from healthy donors and from patients with CF homozygous for either F508del or class I CFTR mutations to assess SLC26A9-mediated chloride secretion by short-circuit current measurements and to study the effect of pharmacological inhibition of SLC26A9 on mucociliary transport (MCT) velocity via time-lapse video microscopy. Inhibition with either S9-A13 or CFTRinh172 showed that SLC26A9 and CFTR contributed to basal (∆Isc=-0.55 µA/cm²; -1.74 µA/cm²) and cAMP-stimulated (∆Isc=-2.53 µA/cm²; -6.08 µA/cm²) chloride secretion in healthy HNE, whereas inhibition of both SLC26A9 and CFTR abolished transepithelial chloride secretion. Inhibition of SLC26A9 decreased MCT velocity (2.6 µm/s vs. 22.71 µm/s; p<0.001) in healthy HNE. In CF cultures homozygous for F508del or class I mutations, residual chloride transport was predominantly mediated by SLC26A9. SLC26A9 inhibition decreased MCT velocity (1.85 µm/s vs. 14.87µm/s; p<0.0001) in CF cultures. SLC26A9 and CFTR synergistically regulate transepithelial chloride secretion in healthy airway epithelia. In the CF airway epithelium SLC26A9 is important for residual chloride secretion and mucociliary transport, independent of the CFTR genotype. These findings support that SLC26A9 represents a promising therapeutic target to promote mucociliary clearance in CF and potentially in other muco-obstructive lung diseases.