title: IL-1β-Induced Protection of Keratinocytes against Staphylococcus aureus-Secreted Proteases Is Mediated by Human β-Defensin 2.
abstract: Atopic dermatitis (AD) is a common chronic inflammatory skin disease that results in significant morbidity. A hallmark of AD is disruption of the critical barrier function of upper epidermal layers, causatively linked to environmental stimuli, genetics, and infection, and a critical current target for the development of new therapeutic and prophylactic interventions. Staphylococcus aureus is an AD-associated pathogen producing virulence factors that induce skin barrier disruption in vivo and contribute to AD pathogenesis. We show, using immortalized and primary keratinocytes, that S. aureus protease SspA/V8 is the dominant secreted factor (in laboratory and AD clinical strains of S. aureus) inducing barrier integrity impairment and tight junction damage. V8-induced integrity damage was inhibited by an IL-1β-mediated mechanism, independent of effects on claudin-1. Induction of keratinocyte expression of the antimicrobial/host defense peptide human β-defensin 2 (hBD2) was found to be the mechanism underpinning this protective effect. Endogenous hBD2 expression was required and sufficient for protection against V8 protease-mediated integrity damage, and exogenous application of hBD2 was protective. This modulatory property of hBD2, unrelated to antibacterial effects, gives new significance to the defective induction of hBD2 in the barrier-defective skin lesions of AD and indicates therapeutic potential.
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Wang
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: McHugh
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Ayub
authors.initials: A
authors.lastname: Qureshi
authors.affiliation: School of Chemistry, University of Edinburgh, Edinburgh, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Campopiano
authors.affiliation: School of Chemistry, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Clarke
authors.affiliation: The Roslin Institute and Edinburgh Infectious Diseases, University of Edinburgh, Easter Bush, Midlothian, UK.
authors.forename: J Ross
authors.initials: JR
authors.lastname: Fitzgerald
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Dorin
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Weller
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK. Electronic address: donald.davidson@ed.ac.uk.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000382:microbiology* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000382:microbiology; D010447:Peptide Hydrolases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013207:Staphylococcal Skin Infections / Q000378:metabolism* / Q000473:pathology; D013211:Staphylococcus aureus / Q000201:enzymology / Q000472:pathogenicity*; D023083:beta-Defensins / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D023083:beta-Defensins; D010447:Peptide Hydrolases