Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human β-defensin-3

Background: Individuals with atopic dermatitis (AD) have frequent colonization and infection with Staphylococcus aureus. Rapid elimination of S aureus depends on constitutive synthesis and mobilization of human beta-defensin-3 (HBD-3). Objective: To determine whether keratinocytes in AD, compared with normal, skin are less able to kill S aureus rapidly, and to assess the potential role that abnormally low mobilization of HBD-3 onto S aureus has in this process. Methods: Skin samples from 10 normal individuals and 10 patients with AD were compared for synthesis and mobilization of HBD-3 onto surface-associated S aureus. Furthermore, keratinocytes from 10 individuals were studied for the effects of T(H)2 cytokines on the ability of the cells to synthesize and mobilize HBD-3, and to kill S aureus. Results: Keratinocytes in skin biopsies from subjects with AD were defective in killing S aureus relative to normal individuals (P <.001). The constitutive levels of HBD-3 in the epidermal keratinocytes were similar between normal individuals and those with AD. However, the cells of patients with AD were unable to mobilize HBD-3 efficiently to kill S aureus. Physiologic Ca++ was essential for development of normal HBD-3 levels by cultured human keratinocytes. Mobilization of HBD-3 and the ability to kill S aureus were significantly (P <.05) inhibited by IL-4 and IL-13. Antagonism of IL-4/10/13 with antibodies significantly (P <.01) improved mobilization of HBD-3 onto the surface of S aureus by skin from patients with AD. Conclusion: Patients with AD have problems with S aureus skin infection. This is a result of increased levels of T(H)2 cytokines, which inhibit keratinocyte mobilization of HBD-3.