Hypoxia Alters Polymeric Immunoglobulin Receptor Expression and Cell Differentiation in the Airway Epithelium

Secretion of immunoglobulin A (IgA), actively transported across the airway epithelium (AE) by the polymeric immunoglobulin receptor (pIgR), represents a key defense of the lung against pathogens. Dysregulation of the IgA/pIgR system has been reported in respiratory diseases, but the underlying mechanism, and particularly the effects of hypoxia, remains poorly characterized. The effects of hypoxia were investigated using the model of human AE reconstituted in vitro upon culture in the air/liquid interface (ALI). AE was exposed to 1% O2, upon resting or inflammatory conditions. Mechanistic studies included pharmacological stabilization of HIF-1α and inhibition of TGF-β signaling. Additionally, HIF-1α and TGF-β pathways were analyzed by multiplex fluorescence immunostaining of lung tissue from patients with acute respiratory distress syndrome (ARDS) and controls. In ALI AE cultures from 22 subjects, hypoxia significantly reduced pIgR expression (mRNA and proteic), regardless of inflammation. Hypoxia also altered AE structure and cell differentiation, leading to a loss of ciliated and goblet cells. Both hypoxia and pharmacological stabilization of HIF-1α recapitulated these effects and induced increased TGF-β2 expression. In lung tissue from ARDS patients, the AE exhibited reduced pIgR expression, associated with increased HIF-1α stabilization and TGF-β2 expression. Hypoxia induced pIgR downregulation and impaired cell differentiation, through HIF-1α stabilization and subsequent autocrine TGF-β2 signaling, providing a novel pathway underlying altered lung IgA immunity in disease.