Attenuated kallikrein-related peptidase activity disrupts desquamation and leads to stratum corneum thickening in human skin equivalent models

McGovern, J.A., Meinert, C., de Veer, S.J., Hollier, B.G., Parker, T.J., & Upton, Z. (2016) Attenuated kallikrein-related peptidase activity disrupts desquamation and leads to stratum corneum thickening in human skin equivalent models. British Journal Of Dermatology. (In Press)

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Abstract

Background

  • Epidermal homeostasis is maintained through the balance between keratinocyte proliferation, differentiation and desquamation, however human skin equivalent (HSE) models are known to excessively differentiate. In native tissue, proteases such as kallikrein-related peptidase (KLK) 5, and KLK7 cleave the extracellular components of corneodesmomes; proteins corneodesmosin (CDSN), desmocollin 1 (DSC1) and desmoglein 1 (DSG1), loosening the cellular connections and enabling desquamation. The actions of KLK7 are tightly controlled by protease inhibitors; skin-derived antileukoproteinase (SKALP), and lympho-epithelial Kazal-type-related inhibitor (LEKTI) which also inhibits KLK5, localising protease activity to the stratum corneum.

Objectives

  • To investigate the mechanisms which inhibit the desquamation cascade in HSE models.

Methods

  • Human skin tissue and HSE models were investigated using gene microarray, real-time PCR, immunohistochemistry, and Western blot analysis to examine key components of the desquamation pathway. To elucidate proteolytic activity in both HSEs and native skin, in situ and gel zymography was performed.

Results

  • Histological analysis indicated that HSE models form a well-organised epidermis, yet develop an excessively thick and compact stratum corneum. Gene microarray analysis revealed that the desquamation cascade was dysregulated in HSE models and this was confirmed using real-time PCR and immunohistochemistry. Immunohistochemistry and Western blot indicated overexpression of LEKTI and SKALP in HSEs. Although KLK7 was also highly expressed in HSEs, zymography indicated that protease activation and activity was lower than in native skin.

Conclusions

  • These findings demonstrate that stratum corneum thickening is due to inhibited KLK5 and KLK7 activation and a subsequent lack of corneodesmosomes degradation in the HSE model epidermis.

Impact and interest:

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ID Code: 97826
Item Type: Journal Article
Refereed: Yes
Keywords: Desquamation, Kallikrein-related peptidase 5, Kallikrein-related peptidase 7, Human skin equivalent, Stratum corneum thickening
DOI: 10.1111/bjd.14879
ISSN: 0007-0963
Divisions: Current > Schools > School of Biomedical Sciences
Current > Schools > School of Chemistry, Physics & Mechanical Engineering
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Current > QUT Faculties and Divisions > Science & Engineering Faculty
Copyright Owner: Copyright 2016 John Wiley & Sons Inc
Deposited On: 01 Aug 2016 23:02
Last Modified: 07 Aug 2016 04:30

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