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: Hyosun Jang, Akira Matsuda, Kyungsook Jung, Kaoru Karasawa, Kenshiro Matsuda, Kumiko Oida, Saori Ishizaka, Ginnae Ahn, Yosuke Amagai, Changjong Moon, Sung-Ho Kim, Peter D Arkwright, Kenji Takamori, Hiroshi Matsuda, Akane Tanaka
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 136 Issue 1 Pg. 127-35 (Jan 2016) ISSN: 1523-1747 [Electronic] United States
• PMID: 26763432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Filaggrin Proteins
• Intermediate Filament Proteins
• Receptor, PAR-2
• Kallikreins
• Klk5 protein, mouse
• Thymic Stromal Lymphopoietin
• TSLP protein, mouse

Topics

• Animals
• Biopsy, Needle
• Cytokines (metabolism)
• Dermatitis, Atopic (immunology, pathology, physiopathology)
• Disease Models, Animal
• Filaggrin Proteins
• Hydrogen-Ion Concentration
• Immunohistochemistry
• Intermediate Filament Proteins (metabolism)
• Kallikreins (metabolism)
• Mice
• Mice, Inbred C57BL
• Receptor, PAR-2 (metabolism)
• Sensitivity and Specificity
• Skin Absorption (physiology)
• Thymic Stromal Lymphopoietin