title: Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum.
abstract: BACKGROUND
  The tight junction (TJ) barrier is located in the granular layer of the epidermis. Filaggrin deficiency predisposes patients to atopic dermatitis (AD) by impairing stratum corneum (SC) barrier function. Altered TJ barrier function has been observed in the skin of patients with AD; however, it remains unclear whether TJ function is influenced by filaggrin deficiency directly or secondarily via skin inflammation.
  
  
  OBJECTIVE
  To investigate the in vivo effects of filaggrin deficiency and skin inflammation on epidermal TJ function.
  
  
  METHODS
  Morphological changes in the TJ were investigated in filaggrin knockout mice and mice with hapten-induced dermatitis using en face visualization of epidermal sheets, and functional changes in the TJ were assessed with an in vivo permeation assay using tracers of various sizes.
  
  
  RESULTS
  In filaggrin knockout mice, there was no apparent change in the honeycomb morphology of the TJ, TJ component mRNA expression, or TJ barrier function in neonates and adults, indicating that filaggrin-deficiency had no direct effects on the TJ. By contrast, in mice with hapten-induced dermatitis, the mRNA expression of TJ components was decreased markedly and the TJ barrier function was size-dependently impaired: the TJ leaked small tracers (<5 kDa), but not large tracers (>30 kDa).
  
  
  CONCLUSIONS
  Filaggrin deficiency did not affect the epidermal TJ barrier directly, but once dermatitis occurred, the skin inflammation induced TJ dysfunction. Since TJ dysfunction induces the SC barrier impairment, skin inflammation will enhance skin permeability to external antigens and result in a vicious cycle of barrier dysfunction and skin inflammation.
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Nerima General Hospital, 1-24-1 Asahigaoka, Nerima-ku, Tokyo 176-8530, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Yokouchi
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan. Electronic address: akiharu@keio.jp.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Kubo
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-Ku, Tokyo 108-8642, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Dermatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Dermatology, School of Medicine Toho University, 5-21-16 Omori-nishi, Tokyo 143-8540, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Division of Cerebral Structure, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Furuse
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan; KOSÉ Endowed Program for Skin Care and Allergy Prevention, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D000818:Animals; D001710:Biotin / Q000737:chemistry; D003876:Dermatitis, Atopic / Q000276:immunology; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D006241:Haptens / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010539:Permeability; D012867:Skin / Q000276:immunology; D019108:Tight Junctions / Q000276:immunology*
chemical_list: D000091344:Filaggrin Proteins; D006241:Haptens; D007381:Intermediate Filament Proteins; D001710:Biotin
keywords: Atopic dermatitis; Barrier deficiency; Filaggrin; Stratum corneum; Tight junction