Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma

Abstract

Background Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear. Objectives To test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is down regulated by IL-13, and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. Methods Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and asthmatics. In the asthmatics, claudin-18 levels were compared with a three-gene-mean marker of TH2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild type mice following aspergillus sensitization. Results Epithelial brushings from asthmatic subjects (n=67) had significantly lower claudin-18 mRNA levels than healthy controls (n=42). Claudin-18 levels were lowest among TH2-high asthmatics. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization. Conclusions These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, TH2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness.

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

“…Asthmatic epithelium is characterized by an increase in basal and goblet cells 18 and a decrease in terminally differentiated ciliated cells, frequently accompanied by basement membrane thickening 19, 20 and epithelial shedding with the formation of Creola bodies consisting of clusters of shed epithelium (even in mild forms of disease) 21–23 . Disruption of epithelial tight and adherens junctions is typical for asthma, with marked loss of E-cadherin 24 and claudin-18 25 . The underlying extracellular matrix, which supports homeostasis and repair of the epithelium, also undergoes significant remodeling, characterized by increased deposition of provisional matrix components, such as the glycoproteins fibronectin 26 , periostin 27 , tenascin-C 28, 29 , hyaluronan and versican 30 .…”

Tight junctions in pulmonary epithelia during lung inflammation

“…In Calu3 cells, IL-4 induces disassembly of TJ molecules [100], IL-4 and IL-13 increase paracellular permeability in human bronchial epithelial cells [107, 118], in sinosonal epithelial cells [142] and in air-liquid interface cultivated paranasal sinus mucosa cells [16]. Although IL-4 and IL-13 show similar effects on TJ in these airway epithelial cell models, depending on the investigated model, they act via different pathways.…”

“…Epithelial brush samples from asthma patients with high IL-13 levels and IL-13-exposed human bronchial epithelial cells showed decreased cldn18.1 levels [118]. In mouse, lung IL-13 reduces cldn18 while increasing cldn4 expression [118].…”

The Role of the Sinonasal Epithelium in Allergic Rhinitis

“…For example, single nucleotide polymorphisms in claudin-1, protocadherin-1, and E-cadherin have been linked to atopic dermatitis, asthma, and Crohn’s disease 11–13 . Decreased claudin-18 expression has been reported in asthmatic patients and claudin-18 knockout mice demonstrate significantly increased airway responsiveness following intranasal aspergillus sensitization 14 . Decreased barrier function and decreased expression of ZO-1, claudin-1, and occludin have been noted in biopsy specimens from patients with CRS with nasal polyps 15–16 .…”