Tight Junction Defects in Atopic Dermatitis

By A. de Benedetto, N. Rafaels, Laura Y. McGirt, A. Ivanov, S. Georas, C. Cheadle, Alan E. Berger, Kunzhong Zhang, S. Vidyasagar, Takeshi Yoshida and 11 more. Journal of Allergy and Clinical Immunology, 2010

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Background Atopic dermatitis (AD) is characterized by dry skin and a hyperreactive immune response to allergens, two cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJ) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. Objective We evaluated the expression/function of the TJ protein, claudin-1 in epithelium from AD and nonatopic (NA) subjects and screened two American populations for SNPs in CLDN1. Methods Expression profiles of nonlesional epithelium from extrinsic AD, NA and psoriasis subjects were generated using Illumina’s BeadChips. Dysregulated intercellular proteins were validated by tissue staining and qPCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed using a knockdown approach in primary human keratinocytes (PHK). Twenty seven haplotype-tagging SNPs in CLDN1 were screened in two independent AD populations. Results We observed strikingly reduced expression of the TJ proteins claudin-1 and -23 only in AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with Th2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro, we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging single nucleotide polymorphisms revealed associations with AD in two North American populations. Conclusion Taken together, these data suggest that an impaired epidermal TJ is a novel feature of skin barrier dysfunction and immune dysregulation observed in AD, and that CLDN1 may be a new susceptibility gene in this disease.

Subfields: Dermatology, Gastroenterology, Neurology

View Paper: https://www.semanticscholar.org/paper/9f286f6109ffbe02aa414d0f2d766b8354a61d69

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Citations in the corpus

Role of Lactobacillus reuteri in Human Health and Diseases (2018, result): “In children with atopic dermatitis, where the impairment of intestinal barrier function has been positively correlated with disease pathogenesis (De Benedetto et al., 2011), treatment with L. reuteri DSM 12246 (and L. rhamnosus 19070-2) significantly reduced the frequency of GI symptoms while…”
Th2 Cytokines and Atopic Dermatitis (2011, result): “Recently, impaired epidermal expression of claudin-1 has been reported in non-lesional skin of AD patients compared to psoriasis patients and non-atopic controls with a concomitant association with disease severity [9].”