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

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• 作者：Kelly Sweerus ; MD^a ; ^b ; ^&lowast ; ; Marrah Lachowicz-Scroggins ; PhD^a ; ^c ; ^&lowast ; ; Erin Gordon ; MD^a ; Michael LaFemina ; MD^a ; ^b ; Xiaozhu Huang ; MD^a ; ^c ; Mihir Parikh ; MD^a ; ^b ; Cindy Kanegai ; MD^a ; John V. Fahy ; MD^a ; ^c ; James A. Frank ; MD^a ; ^b ; ^{James.frank@ucsf.edu}
• 关键词：Asthma ; epithelium ; epithelial barrier function ; tight junction ; antigen sensitization ; airway hyperresponsiveness
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：72-81.e1
• 全文大小：1476 K
• 卷排序：139

文摘

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.ObjectivesWe 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.MethodsClaudin-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.ResultsEpithelial 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.ConclusionsThese 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.