Expression of SLC26A9 in Airways and Its Potential Role in Asthma.

Raquel Centeio,Karl Kunzelmann,Rainer Schreiber,Jiraporn Ousingsawat

doi:10.3390/ijms23062998

Raquel Centeio, Karl Kunzelmann + Show 2 more

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https://doi.org/10.3390/ijms23062998

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Abstract

SLC26A9 is an epithelial anion transporter with a poorly defined function in airways. It is assumed to contribute to airway chloride secretion and airway surface hydration. However, immunohistochemistry showing precise localization of SLC26A9 in airways is missing. Some studies report localization near tight junctions, which is difficult to reconcile with a chloride secretory function of SLC26A9. We therefore performed immunocytochemistry of SLC26A9 in sections of human and porcine lungs. Obvious apical localization of SLC26A9 was detected in human and porcine superficial airway epithelia, whereas submucosal glands did not express SLC26A9. The anion transporter was located exclusively in ciliated epithelial cells. Highly differentiated BCi-NS1 human airway epithelial cells grown on permeable supports also expressed SLC26A9 in the apical membrane of ciliated epithelial cells. BCi-NS1 cells expressed the major Cl− transporting proteins CFTR, TMEM16A and SLC26A9 in about equal proportions and produced short-circuit currents activated by increases in intracellular cAMP or Ca2+. Both CFTR and SLC26A9 contribute to basal chloride currents in non-stimulated BCi-NS1 airway epithelia, with CFTR being the dominating Cl− conductance. In wtCFTR-expressing CFBE human airway epithelial cells, SLC26A9 was partially located in the plasma membrane, whereas CFBE cells expressing F508del-CFTR showed exclusive cytosolic localization of SLC26A9. Membrane localization of SLC26A9 and basal chloride currents were augmented by interleukin 13 in wild-type CFTR-expressing cells, but not in cells expressing the most common disease-causing mutant F508del-CFTR. The data suggest an upregulation of SLC26A9-dependent chloride secretion in asthma, but not in the presence of F508del-CFTR.

Highlights

The epithelial anion transporter SLC26A9 possibly contributes to airway surface hydration by operating as an uncoupled Cl− transporter [1,2]
This corresponds to several earlier studies indicating a lack of proper biosynthesis and apical expression of SLC26A9 in cultured cystic fibrosis (CF) airway epithelial cells [14,22–24]
SLC26A9 Is Expressed in the Apical Membrane of the Airway Epithelium

Summary

Introduction

The epithelial anion transporter SLC26A9 (solute carrier 26 family member A9) possibly contributes to airway surface hydration by operating as an uncoupled Cl− transporter [1,2]. SLC26A9, together with the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca2+ activated Cl− channel TMEM16A, is among the most important secretory Cl− pathways in airways. SLC26A9 was suggested to have a role in inflammatory airway diseases, such as cystic fibrosis (CF) and asthma [3–5]. SLC26A9 belongs to a family of 10 paralogous mammalian proteins that play a role in tissue-specific ion transport, except of prestin, which mediates electromotility in inner ear outer hair cells [6–9]. Operating as a chloride transporter rather than a channel, SLC26A9 allows for high Cl− transport rates and substantial anion currents [1]. The aim of the present study was to examine the contribution of SLC26A9 to airway chloride secretion

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