ATP12A promotes mucus dysfunction during Type 2 airway inflammation

Alison T Lennox,Timothy E Corcoran,Elisa M Heidrich,Sally E Wenzel,John A Leech,Mike M Myerburg,Joseph M Pilewski,Stefanie L Coburn,Thomas R Kleyman

doi:10.1038/s41598-018-20444-8

Alison T Lennox, Timothy E Corcoran + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-20444-8

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Abstract

Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport properties of airway epithelium. However, these electrophysiological changes cannot explain the thick, tenacious airway mucus that characterizes the clinical phenotype. Here we report that IL-13 dramatically increases the airway surface liquid (ASL) viscosity in cultured primary human bronchial epithelial cells and thereby inhibits mucus clearance. These detrimental rheological changes require ATP12A, a non-gastric H+/K+-ATPase that secretes protons into the ASL. ATP12A knockdown or inhibition prevented the IL-13 dependent increase in ASL viscosity but did not alter the ASL pH. We propose that ATP12A promotes airway mucus dysfunction in individuals with T2 inflammatory airway diseases and that ATP12A may be a novel therapeutic target to improve mucus clearance.

Highlights

Mucociliary clearance (MCC) is a primary innate defense mechanism of the conducting airways, enabling inhaled particulate matter and pathogens to be expelled[1]
We have previously shown that the airway surface liquid (ASL) forms a meniscus at the interface between the epithelial cell surface and the cell culture transwell filter wall and that this meniscus contains the vast majority of the apical volume
To measure the volume of the ASL contained within the meniscus on height was increased when bronchial epithelial (HBE) cells cultured with IL-13, the cell culture plates were scanned using an optical scanner and the magnitude of the meniscus was measured by analyzing the pattern of light refraction through the fluid[34]

Summary

Introduction

Mucociliary clearance (MCC) is a primary innate defense mechanism of the conducting airways, enabling inhaled particulate matter and pathogens to be expelled[1]. Asphyxiation is often the defining cause of death in cases of fatal asthma, where “extensive obstruction of the conducting airway by tenacious mucus exudates” is described on pathological examination[13,14,15,16]. Despite these significant findings, the mucus dysfunction in allergic airway disease is often underappreciated by clinicians, perhaps because small airway mucus infrequently results in a productive cough. MUC5AC transgenic mice do not spontaneously develop airway disease and have normal MCC, suggesting that increased MUC5AC expression alone is not sufficient to cause mucus dysfunction[27,28,29]

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