title: Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis.
abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1 Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Reitaro
authors.initials: R
authors.lastname: Tokumasu
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Dermatology, Course of integrated Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamaga
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Dermatology, Course of integrated Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Murota
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Koya
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Bando
authors.affiliation: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Department of Dermatology, Course of integrated Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; atsukita@biosci.med.osaka-u.ac.jp.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010539:Permeability; D010641:Phenotype; D055815:Young Adult
chemical_list: D062445:Claudin-1
keywords: atopic dermatitis; claudin-1; tight junctions