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Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.
J Allergy Clin Immunol 2017; 140(5):1310-1322.e5JA

Abstract

BACKGROUND

Upregulation of kallikreins (KLKs) including KLK5 has been reported in atopic dermatitis (AD). KLK5 has biological functions that include degrading desmosomal proteins and inducing proinflammatory cytokine secretion through protease-activated receptor 2 (PAR2). However, due to the complex interactions between various cells in AD inflamed skin, it is difficult to dissect the precise and multiple roles of upregulated KLK5 in AD skin.

OBJECTIVE

We investigated the effect of upregulated KLK5 on the expression of epidermal-related proteins and cytokines in keratinocytes and on skin architecture.

METHODS

Lesional and nonlesional AD skin biopsies were collected for analysis of morphology and protein expression. The relationship between KLK5 and barrier-related molecules was investigated using an ex vivo dermatitis skin model with transient KLK5 expression and a cell model with persistent KLK5 expression. The influence of upregulated KLK5 on epidermal morphology was investigated using an in vivo skin graft model.

RESULTS

Upregulation of KLK5 and abnormal expression of desmoglein 1 (DSG1) and filaggrin, but not PAR2 were identified in AD skin. PAR2 was increased in response to transient upregulation of KLK5, whereas persistently upregulated KLK5 did not show this effect. Persistently upregulated KLK5 degraded DSG1 and stimulated secretion of IL-8, IL-10, and thymic stromal lymphopoietin independent of PAR2 activity. With control of higher KLK5 activity by the inhibitor sunflower trypsin inhibitor G, restoration of DSG1 expression and a reduction in AD-related cytokine IL-8, thymic stromal lymphopoietin, and IL-10 secretion were observed. Furthermore, persistently elevated KLK5 could induce AD-like skin architecture in an in vivo skin graft model.

CONCLUSIONS

Persistently upregulated KLK5 resulted in AD-like skin architecture and secretion of AD-related cytokines from keratinocytes in a PAR2 independent manner. Inhibition of KLK5-mediated effects may offer potential as a therapeutic approach in AD.

Authors+Show Affiliations

Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.Department of Chemistry, University College London, London, United Kingdom.Department of Chemistry, University College London, London, United Kingdom.Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom; Dermatology, University Hospital Southampton National Health Service Foundation Trust, Southampton, United Kingdom.Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom. Electronic address: w.di@ucl.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28238749

Citation

Zhu, Yanan, et al. "Persistent Kallikrein 5 Activation Induces Atopic Dermatitis-like Skin Architecture Independent of PAR2 Activity." The Journal of Allergy and Clinical Immunology, vol. 140, no. 5, 2017, pp. 1310-1322.e5.
Zhu Y, Underwood J, Macmillan D, et al. Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. J Allergy Clin Immunol. 2017;140(5):1310-1322.e5.
Zhu, Y., Underwood, J., Macmillan, D., Shariff, L., O'Shaughnessy, R., Harper, J. I., ... Di, W. L. (2017). Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. The Journal of Allergy and Clinical Immunology, 140(5), pp. 1310-1322.e5. doi:10.1016/j.jaci.2017.01.025.
Zhu Y, et al. Persistent Kallikrein 5 Activation Induces Atopic Dermatitis-like Skin Architecture Independent of PAR2 Activity. J Allergy Clin Immunol. 2017;140(5):1310-1322.e5. PubMed PMID: 28238749.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. AU - Zhu,Yanan, AU - Underwood,Joanne, AU - Macmillan,Derek, AU - Shariff,Leila, AU - O'Shaughnessy,Ryan, AU - Harper,John I, AU - Pickard,Chris, AU - Friedmann,Peter S, AU - Healy,Eugene, AU - Di,Wei-Li, Y1 - 2017/02/24/ PY - 2016/07/12/received PY - 2017/01/16/revised PY - 2017/01/30/accepted PY - 2017/2/28/pubmed PY - 2017/11/29/medline PY - 2017/2/28/entrez KW - Kallikrein 5 KW - SFTI KW - atopic dermatitis KW - serine protease inhibitor KW - skin barrier SP - 1310 EP - 1322.e5 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 140 IS - 5 N2 - BACKGROUND: Upregulation of kallikreins (KLKs) including KLK5 has been reported in atopic dermatitis (AD). KLK5 has biological functions that include degrading desmosomal proteins and inducing proinflammatory cytokine secretion through protease-activated receptor 2 (PAR2). However, due to the complex interactions between various cells in AD inflamed skin, it is difficult to dissect the precise and multiple roles of upregulated KLK5 in AD skin. OBJECTIVE: We investigated the effect of upregulated KLK5 on the expression of epidermal-related proteins and cytokines in keratinocytes and on skin architecture. METHODS: Lesional and nonlesional AD skin biopsies were collected for analysis of morphology and protein expression. The relationship between KLK5 and barrier-related molecules was investigated using an ex vivo dermatitis skin model with transient KLK5 expression and a cell model with persistent KLK5 expression. The influence of upregulated KLK5 on epidermal morphology was investigated using an in vivo skin graft model. RESULTS: Upregulation of KLK5 and abnormal expression of desmoglein 1 (DSG1) and filaggrin, but not PAR2 were identified in AD skin. PAR2 was increased in response to transient upregulation of KLK5, whereas persistently upregulated KLK5 did not show this effect. Persistently upregulated KLK5 degraded DSG1 and stimulated secretion of IL-8, IL-10, and thymic stromal lymphopoietin independent of PAR2 activity. With control of higher KLK5 activity by the inhibitor sunflower trypsin inhibitor G, restoration of DSG1 expression and a reduction in AD-related cytokine IL-8, thymic stromal lymphopoietin, and IL-10 secretion were observed. Furthermore, persistently elevated KLK5 could induce AD-like skin architecture in an in vivo skin graft model. CONCLUSIONS: Persistently upregulated KLK5 resulted in AD-like skin architecture and secretion of AD-related cytokines from keratinocytes in a PAR2 independent manner. Inhibition of KLK5-mediated effects may offer potential as a therapeutic approach in AD. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/28238749/Persistent_kallikrein_5_activation_induces_atopic_dermatitis_like_skin_architecture_independent_of_PAR2_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(17)30315-9 DB - PRIME DP - Unbound Medicine ER -