SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

Abstract

Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl -) secretion plays a role in the disease. However, the molecular mechanism underlying Cl -secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl -channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl -secretion in the airways of wildtype but not Slc26a9-deficient mice. While IL-13-induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3′ UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl -channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl -secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging.

Hypertonic Saline Is Effective in the Prevention and Treatment of Mucus Obstruction, but Not Airway Inflammation, in Mice with Chronic Obstructive Lung Disease

“…This concept is supported by the airway phenotype of the bENaC-overexpressing mouse, which develops spontaneous mucus obstruction caused by constitutive hyperabsorption of airway surface fluid due to an increased activity of ENaC (9,26,27). The concept is also supported by the phenotype of mice lacking the SLC26A9 Cl 2 channel, which show normal ion transport and airway morphology under physiological conditions, but develop airway mucus obstruction due to a reduced capacity to increase Cl 2 and fluid secretion in parallel to mucin hypersecretion in allergic airway disease (8,46).…”

“…Recent results suggest that relative dehydration of airway surfaces, either caused by reduced availability of airway surface liquid due to dysregulated epithelial ion transport, or increased mucin secretion triggered by airway inflammation, generates an abnormally concentrated mucus that impairs mucus clearance and produces airway mucus obstruction in a spectrum of other acute and chronic obstructive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD) (7)(8)(9)(10)(11)(12).…”

CFTR: cystic fibrosis and beyond

“…As mucus hyperconcentration not only results from dysregulated epithelial ion and fluid transport as in CF, but also from increased mucin secretion driven by chronic airway inflammation and infection [39,50], these results suggest that airway surface dehydration may be a common disease mechanism that contributes to the pathogenesis of a broad spectrum of mucostatic airway diseases including asthma and chronic obstructive pulmonary disease (COPD) [20,49]. This concept is supported by recent studies in mice with experimental asthma demonstrating that T-helper cell type 2-induced mucus hypersecretion is associated with a hypersecretory ion transport phenotype that protects ''asthmatic'' wild-type mice from airway mucus obstruction in vivo, whereas mice that lack the epithelial Cl -channel SLC26A9 (solute carrier family 26 member 9), a member of the SLC26 family of anion transporters that is strongly expressed in the lung [51], develop airway mucus obstruction due to a reduced capacity to increase Cl -and fluid secretion in parallel to mucin hypersecretion in allergic airway disease [52,53].…”

“…-secretion is activated in airway inflammation and is essential to prevent airway mucus obstruction in the presence of mucus hypersecretion [52,53]. Furthermore, a functional single nucleotide polymorphism (rs2282430) in the 39 untranslated region of SLC26A9 that reduced protein expression by creating a binding site for a microRNA (has-miRNA-632) was shown to be associated with asthma in children, and SLC26A9 variants were recently detected in patients with non-CF bronchiectasis [113].…”

Small Airways in Asthma: Distal is Different

“…By interaction with different intracellular factors receptor binding of these extracellular ligands triggers movement of the granules along the cytoskeleton to the plasma membrane for exocytosis resulting in the secretion of mucin to the airway lumen [27]. To acquire the ideal viscoelastic property for ciliary clearance mucins absorb more than 100-fold their mass of water after secretion due to the high water binding capacity of their polysaccharides [48,49]. One of the most potent inducers of Muc5Ac and thus of GCM and mucus hypersecretion is IL-13.…”