Glucocorticoids Regulate Tight Junction Permeability of Lung Epithelia by Modulating Claudin 8

Abstract

The lung epithelium constitutes a selective barrier that separates the airways from the aqueous interstitial compartment. Regulated barrier function controls water and ion transport across the epithelium and is essential for maintaining lung function. Tight junctions (TJs) seal the epithelial barrier and determine the paracellular transport. The properties of TJs depend especially on their claudin composition. Steroids are potent drugs used to treat a variety of airway diseases. Therefore, we addressed whether steroid hormones directly act on TJ properties in lung epithelia. Primary human tracheal epithelial cells and NCI-H441 cells, both cultivated under air-liquid interface conditions, were used as epithelial cell models. Our results demonstrate that glucocorticoids, but not mineralocorticoids, decreased paracellular permeability and shifted the ion permselectivity of TJs toward Cl(-). Glucocorticoids up-regulated claudin 8 (cldn8) expression via glucocorticoid receptors. Silencing experiments revealed that cldn8 is necessary to recruit occludin at the TJs. Immunohistochemistry on human lung tissue showed that cldn8 is specifically expressed in resorptive epithelia of the conducting and respiratory airways but not in the alveolar epithelium. We conclude that glucocorticoids enhance lung epithelia barrier function and increase paracellular Cl(-) selectivity via modulation of cldn8-dependent recruitment of occludin at the TJs. This mode of glucocorticoid action on lung epithelia might be beneficial to patients who suffer from impaired lung barrier function in various diseased conditions.

Tight junctions in pulmonary epithelia during lung inflammation

“…1b). Immunohistological experiments revealed that the epithelia of cartilaginous and non-cartilaginous airways is positive for cldn1, cldn2, cldn3, cldn4, cldn5, cldn7 and cldn8 [24, 62, 63, 66]. However, the intracellular localisation of these claudins differs.…”

“…Cldn2 is localised in intracellular stores rather than in apico-lateral TJ complexes [62]. In contrast, cldn3, cldn5 and cldn8 were detected exclusively in TJ complexes [24, 66], and cldn1 and cldn4 localise throughout the lateral membranes as well as to the apico-lateral TJ complexes [24]. Cldn7 localises at the lateral membranes basolateral of the TJ complex [24].…”

“…Investigation of cldn8 function in the lung is rather sparse. Immnunohistochemical experiments revealed that cldn8 localises along conductive and respiratory airway epithelia, where it accumulates apico-laterally at the TJs [66]. In the alveolar epithelium, cldn8 staining revealed a faint and cytoplasmic staining in some alveolar type II cells [66].…”

“…Immnunohistochemical experiments revealed that cldn8 localises along conductive and respiratory airway epithelia, where it accumulates apico-laterally at the TJs [66]. In the alveolar epithelium, cldn8 staining revealed a faint and cytoplasmic staining in some alveolar type II cells [66]. In the airway epithelium, cldn8 is up-regulated by glucocorticoids but not by mineralocorticoids [66].…”

Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

“…Claudins are tetraspanin transmembrane proteins that interact with structural proteins to form the barrier that impacts the selective permeability observed between epithelial cells [20,21]. Cldn-3 and Cldn-18 [11,22] are family members abundantly expressed in the lung; however, additional Cldn proteins have been implicated in lung development and in the maintenance of normal lung physiology [20,23,24,25]. …”