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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Sweerus, Kelly^1,2,3  Lachowicz-Scroggins, Marrah^1,4  Gordon, Erin¹  LaFemina, Michael^1,2,3  Huang, Xiaozhu^1,4  Parikh, Mihir^1,2,3  Kanegai, Cindy¹  Fahy, John V.^1,4  Frank, James A.^1,2,3 

[1] Univ Calif San Francisco, Div Pulm Crit Care Sleep & Allergy Med, San Francisco, CA 94143 USA

[2] San Francisco VA Med Ctr, San Francisco, CA USA

[3] Northern Calif Inst Res & Educ, San Francisco, CA USA

[4] Univ Calif San Francisco, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA

关键词: Asthma;    epithelium;    epithelial barrier function;    tight junction;    antigen sensitization;    airway hyperresponsiveness;   

DOI  :  10.1016/j.jaci.2016.02.035

来源: Elsevier

【 摘 要 】

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: 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. Methods: 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 T(H)2 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 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 T(H)2-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. Conclusions: These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, T(H)2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness.

【 授权许可】

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