IL-1beta-induced protection of keratinocytes against Staphylococcus aureus-secreted proteases is mediated by human beta defensin 2.
Wang, B.*, McHugh, B. J.*, Qureshi, A.*, Campopiano, D. J., Clarke, D. J., Fitzgerald, J. R., Dorin, J. R., Weller, R., Davidson, D. J. J. Invest. Derm. (2017) 137(1):95-105. PubMed
Davidson lab supported by funding from: MRC & China Scholarship Council
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 an IL-1?-mediated mechanism, independent of effects on claudin-1. Induction of keratinocyte expression of the antimicrobial / host defence peptide human beta 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.