Soluble E-Cadherin Contributes to Airway Inflammation in Severe Asthma.

Abstract

Impaired airway epithelial barrier and decreased expression of E-cadherin are key features of severe asthma. As a gatekeeper of the mucosa, E-cadherin can be cleaved from the cell surface and released into the apical lumen in soluble form. The aim of this study was to investigate the role of soluble E-cadherin (sE-cadherin) in severe asthma. Induced sputum was obtained from healthy subjects and patients with asthma. Two murine models of severe asthma were established using either toluene diisocyanate or ovalbumin/complete Freund's adjuvant. The role of sE-cadherin in severe asthma was evaluated by intraperitoneal injection of DECMA-1, a neutralizing antibody against sE-cadherin. Mice or THP-1-derived macrophages were treated with recombinant sE-cadherin to explore the proinflammatory mechanism of sE-cadherin. Patients with severe asthma had significantly higher sputum sE-cadherin concentrations than healthy subjects and those with mild to moderate asthma, which were positively correlated with sputum HMGB1 concentration and the glucocorticoid dose required for daily control. Allergen exposure markedly increased sE-cadherin concentration in the BAL fluid in mice. Treatment with DECMA-1 significantly attenuated allergen-induced airway inflammation and hyperresponsiveness in both models of severe asthma. In contrast, exposure to recombinant sE-cadherin dramatically upregulated VEGF expression in THP-1-derived macrophages and increased neutrophil and eosinophil infiltration into the airway, as well as the release of VEGF and IL-6 in mice, both of which can be suppressed by pharmacological inhibition of ERK signaling. Taken together, our data indicate that sE-cadherin contributes to airway inflammation in severe asthma in an ERK-dependent pathway.