Claudin-1 Mediated Tight Junction Dysfunction as a Contributor to Atopic March

Abstract

Atopic march refers to the phenomenon wherein the occurrence of asthma and food allergy tends to increase after atopic dermatitis. The mechanism underlying the progression of allergic inflammation from the skin to gastrointestinal (GI) tract and airways has still remained elusive. Impaired skin barrier was proposed as a risk factor for allergic sensitization. Claudin-1 protein forms tight junctions and is highly expressed in the epithelium of the skin, airways, and GI tract, thus, the downregulation of claudin-1 expression level caused by CLDN-1 gene polymorphism can mediate common dysregulation of epithelial barrier function in these organs, potentially leading to allergic sensitization at various sites. Importantly, in patients with atopic dermatitis, asthma, and food allergy, claudin-1 expression level was significantly downregulated in the skin, bronchial and intestinal epithelium, respectively. Knockdown of claudin-1 expression level in mouse models of atopic dermatitis and allergic asthma exacerbated allergic inflammation, proving that downregulation of claudin-1 expression level contributes to the pathogenesis of allergic diseases. Therefore, we hypothesized that the tight junction dysfunction mediated by downregulation of claudin-1 expression level contributes to atopic march. Further validation with clinical data from patients with atopic march or mouse models of atopic march is needed. If this hypothesis can be fully confirmed, impaired claudin-1 expression level may be a risk factor and likely a diagnostic marker for atopic march. Claudin-1 may serve as a valuable target to slowdown or block the progression of atopic march.

Keywords: asthma; atopic dermatitis; atopic march; claudin-1; epithelial barrier; food allergy.

Figure 1

Claudin-1-mediated tight junction dysfunction contributes to the atopic march. The synergic effect of CLDN-1 gene polymorphism and environmental factors lead to common disturbance of claudin-1 in the epithelium of skin, airways and GI tract, causing tight junction dysfunction and impaired epithelial barrier function in these organs. Entry of allergens through damaged skin barrier leads to the systemic type 2 inflammation in patients with AD, which further downregulates the claudin-1 expression level in the GI tract and airways. This exacerbation of barrier impairment in the intestinal and airway epithelium finally leads to the progression of allergic inflammation from skin to the GI tract and then to airways. GI, gastrointestinal; Th2 cell, Type 2 helper T cell; B cell, B lymphocyte; IgE, immunoglobulin E; IL-4, interleukin 4; IL-5, interleukin-5; IL-13, interleukin-13. Granules, granules secreted by basophils containing mediators of inflammation.

Figure 2

CLDN-1 expression level in the epithelial tissue of patients with allergic diseases. CLDN-1 expression level was downregulated in the epithelium of skin, airways, and GI tract in patients with AD, asthma, and EoE, respectively. (A) CLDN-1 mRNA expression in lesional skin of AD patients (n=52) and healthy controls (n = 20). (B) CLDN-1 mRNA expression in bronchial epithelium of patients with severe asthma (n = 31) and healthy controls (n = 17). (C) CLDN-1 mRNA expression in esophageal epithelium of patients with EoE (n = 4) and healthy controls (n = 5). * P < 0.05; **** P < 0.0001 by Mann-Whitney U test. Error bars indicate SEM. AD, atopic dermatitis; EoE, eosinophilic esophagitis.