title: Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.
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.affiliation: Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Underwood
authors.affiliation: Department of Chemistry, University College London, London, United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Macmillan
authors.affiliation: Department of Chemistry, University College London, London, United Kingdom.
authors.forename: Leila
authors.initials: L
authors.lastname: Shariff
authors.affiliation: Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Shaughnessy
authors.affiliation: Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
authors.affiliation: Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Pickard
authors.affiliation: Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Friedmann
authors.affiliation: 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.
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
authors.affiliation: 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.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Di
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology*; D051183:Desmoglein 1 / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism*; D000091344:Filaggrin Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000276:immunology*; D044464:Receptor, PAR-2; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012867:Skin / Q000276:immunology* / Q000473:pathology; D016038:Skin Transplantation; D014361:Trypsin Inhibitors / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D051183:Desmoglein 1; C000621508:F2RL1 protein, human; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018836:Inflammation Mediators; D007381:Intermediate Filament Proteins; D044464:Receptor, PAR-2; D043562:Receptors, G-Protein-Coupled; D014361:Trypsin Inhibitors; C400147:KLK5 protein, human; D007610:Kallikreins
keywords: Kallikrein 5; SFTI; atopic dermatitis; serine protease inhibitor; skin barrier