Interleukin-Mediated Pendrin Transcriptional Regulation in Airway and Esophageal Epithelia

Abstract

Pendrin (SLC26A4), a Cl^-/anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in other tissues, such as airways and esophageal epithelia, where it is transcriptionally regulated by the inflammatory cytokines interleukin (IL)-4 and IL-13 through a signal transducer and activator of transcription 6 (STAT6)-mediated pathway. In the airway epithelium, increased pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated pendrin expression is supposed to impact the intracellular pH regulation system. In this review, we discuss some of the recent findings on interleukin-mediated transcriptional regulation of pendrin and how this dysregulation impacts airway and esophagus epithelial homeostasis during inflammatory diseases.

Keywords: airway epithelium; asthma; eosinophilic esophagitis; esophageal epithelium; interleukins; pendrin.

Figure 1

Schematic model for airway surface liquid (ASL) thickness regulation (modified from References [22,96]). In airway epithelial cells, interleukin (IL)-4 and IL-13 increase Cl⁻ secretion acting on expression and/or activity of cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs) while decreasing Na⁺ reabsorption through epithelium sodium channels (EnaCs). This would result in a higher ion concentration in the lumen, with water following the osmotic gradient and increasing ASL thickness. IL-4 and IL-13, however, increase pendrin expression, thus leading to Cl⁻ reabsorption and HCO₃⁻ secretion. HCO₃⁻ is then combined with H⁺ and transformed to CO₂ and H₂O by the carbonic anhydrase (CA) enzymes in the lumen, leading to net water reabsorption and eventually decreasing ASL thickness.

Figure 2

Schematic model for mucus secretion in bronchial epithelial cells (modified from Reference [132]). Na⁺–K⁺–Cl⁻ co-transporter (NKCC1) promotes the basolateral absorption of Cl⁻, which is then secreted into the lumen by CFTR and anoctamin 1 (ANO1), while pendrin exchanges Cl⁻ from the lumen with intracellular HCO₃⁻. This equilibrium is dysregulated by inflammatory events, with an increased HCO₃⁻ secretion leading to higher mucus formation. For graphic simplicity, all the transporters are shown in the same cell, although they may be expressed in different cells of the airway epithelium.

Figure 3

Schematic model for intracellular pH regulatory circuit in normal and eosinophilic esophagitis (EE) stratified squamous esophageal epithelial cells (modified from Reference [152]). In normal epithelium, intracellular pH is kept balanced by the presence of Na⁺-driven Cl⁻/HCO₃⁻ exchanger (NCBE), Na⁺/H⁺ exchanger (NHE3), and HCO₃⁻/Cl⁻ exchangers (pendrin (PDS), SLC4A2. And SLC4A8). During IL-13 inflammatory conditions in EE, expression of pendrin and NHE3 is increased, leading to unbalanced pH and water influx causing dilated intercellular spaces (DIS) and epithelium disruption.