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      Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

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          Significance

          Claudin-1 ( CLDN1), which is thought to be a key gene for human skin disease, especially atopic dermatitis (AD), encodes the dominant claudin responsible for the paracellular barrier at tight junctions in the epidermis. Although decreased CLDN1 expression levels are reported in AD patients, it has been difficult to study how CLDN1 contributes to AD development, mainly because Cldn1 knock-out mice die within 1 d after birth from dehydration. In this report, we reproduced features of human AD in mice, by systematically regulating the Cldn1 expression level. Our experimental approach contributes to the understanding of AD’s etiology and suggests a therapeutic target for this disorder.

          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.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          12 July 2016
          24 June 2016
          : 113
          : 28
          : E4061-E4068
          Affiliations
          [1] aLaboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University , 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
          [2] bDepartment of Dermatology, Course of integrated Medicine, Graduate School of Medicine, Osaka University , 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
          [3] cLewis–Sigler Institute for Integrative Genomics, Princeton University , Princeton, NJ 08544;
          [4] dLaboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology , 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan
          Author notes
          1To whom correspondence should be addressed. Email: atsukita@ 123456biosci.med.osaka-u.ac.jp .

          Edited by Mina Bissell, E. O. Lawrence Berkeley National Laboratory, Berkeley, CA, and approved May 17, 2016 (received for review December 23, 2015)

          Author contributions: R.T., Y.Y., H.M., and S.T. designed research; R.T., K.Y., Y.Y., and K.S. performed research; R.T., Y.Y., K.B., and Y.F. contributed new reagents/analytic tools; R.T., K.Y., Y.Y., H.M., K.S., A.T., I.K., and S.T. analyzed data; and R.T., Y.Y., H.M., and S.T. wrote the paper.

          Article
          PMC4948351 PMC4948351 4948351 201525474
          10.1073/pnas.1525474113
          4948351
          27342862
          e0a7df9d-4e01-4680-a64c-b79b8334df35
          History
          Page count
          Pages: 8
          Funding
          Funded by: Ministry of Education, Culture, Sports, Science, and Technology (MEXT) 501100001700
          Award ID: 24247037
          Funded by: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (CREST, JST) 501100003382
          Award ID: NA
          Funded by: Japan Society for the Promotion of Science (JSPS) 501100001691
          Award ID: 12J04387
          Categories
          PNAS Plus
          Biological Sciences
          Medical Sciences
          PNAS Plus

          claudin-1,tight junctions,atopic dermatitis
          claudin-1, tight junctions, atopic dermatitis

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