skin barrier homeostasis in atopic dermatitis feedback regulation of kallikrein activity特应性皮炎皮肤屏障内稳态激肽释放酶活动的反馈调节.pdfVIP

Skin Barrier Homeostasis in Atopic Dermatitis: Feedback Regulation of Kallikrein Activity 1 2,3 4 Reiko J. Tanaka *, Masahiro Ono , Heather A. Harrington 1 Department of Bioengineering, Imperial College London, London, United Kingdom, 2 Immunobiology Unit, Institute of Child Health, University College London, London, United Kingdom, 3 Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 4 Division of Molecular Biosciences, Imperial College London, London, United Kingdom Abstract Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external