title: Skin pH Is the Master Switch of Kallikrein 5-Mediated Skin Barrier Destruction in a Murine Atopic Dermatitis Model.
abstract: Elevated skin surface pH has been reported in patients with atopic dermatitis. In this study, we explored the role of skin pH in the pathogenesis of atopic dermatitis using the NC/Tnd murine atopic dermatitis model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free conditions induced kallikrein 5 and activated protease-activated receptor 2, resulting in thymic stromal lymphopoietin secretion and a cutaneous T-helper 2 allergic response. This was associated with increased transepidermal water loss and development of eczematous lesions in these specific pathogen-free NC/Tnd mice, which normally do not suffer from atopic dermatitis. Injection of recombinant thymic stromal lymphopoietin also induced scratching behavior in the specific pathogen-free NC/Tnd mice. Thymic stromal lymphopoietin production and dermatitis induced by alkalinization of the skin could be blocked by the protease-activated receptor 2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein 5 activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger 1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate kallikrein 5 activity leading to skin barrier dysfunction, itch, and dermatitis via the protease-activated receptor 2-thymic stromal lymphopoietin pathway.
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Hyosun
authors.initials: H
authors.lastname: Jang
authors.affiliation: Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Kyungsook
authors.initials: K
authors.lastname: Jung
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Karasawa
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Oida
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Ishizaka
authors.affiliation: Laboratory of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Ginnae
authors.initials: G
authors.lastname: Ahn
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Amagai
authors.affiliation: College of Veterinary Medicine and Veterinary Medical Research Institute, Chonnam National University, Gwangju, South Korea.
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.affiliation: College of Veterinary Medicine and Veterinary Medical Research Institute, Chonnam National University, Gwangju, South Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School, Urayasu, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan; Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan. Electronic address: hiro@cc.tuat.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan; Laboratory of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan. Electronic address: akane@cc.tuat.ac.jp.
authors.forename: Akane
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D000091344:Filaggrin Proteins; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D007610:Kallikreins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012680:Sensitivity and Specificity; D012869:Skin Absorption / Q000502:physiology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D044464:Receptor, PAR-2; D007610:Kallikreins; C495973:Klk5 protein, mouse; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse