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

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 1; pp. 72 - 81.e1
• Main Authors: Sweerus, Kelly, Lachowicz-Scroggins, Marrah, Gordon, Erin, LaFemina, Michael, Huang, Xiaozhu, Parikh, Mihir, Kanegai, Cindy, Fahy, John V., Frank, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017; Elsevier Limited
• Subjects: Adult; airway hyperresponsiveness; Allergy and Immunology; Animals; antigen sensitization; Antigens, Fungal - immunology; Arylsulfonates - metabolism; Aspergillus - immunology; Asthma; Asthma - blood; Asthma - metabolism; Asthma - pathology; Asthma - physiopathology; Cell Line; Cells, Cultured; Claudins - deficiency; Claudins - genetics; Claudins - metabolism; epithelial barrier function; epithelium; Genes; Hogs; Humans; Immunoglobulin E - blood; Interleukin-13 - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mucous membrane; Permeability; Respiratory Mucosa - metabolism; Respiratory System - cytology; Respiratory System - metabolism; Respiratory System - pathology; Respiratory System - physiopathology; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Rodents; Small intestine; tight junction; Young Adult; airway hyperresponsiveness; PAS; Papp; UCSF; antigen sensitization; epithelium; OVA; epithelial barrier function; GAPDH; tight junction; Asthma; Glyceraldehyde 3-phosphate dehydrogenase; Ovalbumin; P app; University of California, San Francisco; Periodic acid–Schiff; Apparent permeability
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.02.035

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. We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, 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. Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among TH2-high patients with asthma. 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. 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.