IL-1beta-induced protection of keratinocytes against Staphylococcus aureus-secreted proteases is mediated by human beta defensin 2

Atopic Dermatitis (AD) is a common chronic inflammatory skin disease, resulting 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. S. aureus is an AD-associated pathogen producing virulence factors which induce skin barrier disruption in vivo and contribute to AD pathogenesis. We demonstrate, using immortalised 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 a novel IL-1β-mediatedmechanism, independent of effects on claudin-1. Induction of keratinocyte expression
of the antimicrobial / host defence peptide human beta defensin 2 (hBD2) was foundto be the mechanism underpinning this protective effect. Endogenous hBD2expression was required and sufficient for protection against V8 protease-mediatedintegrity damage, and exogenous application of hBD2 was protective. This novelmodulatory property of hBD2, unrelated to antibacterial effects, gives newsignificance to the defective induction of hBD2 in the barrier-defective skin lesions ofAD, and indicates novel therapeutic potential.