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

  • Kevin O. Kisich
    Affiliations
    Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo

    Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
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  • Charles W. Carspecken
    Affiliations
    Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo

    Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
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  • Stephanie Fiéve
    Affiliations
    Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
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  • Mark Boguniewicz
    Affiliations
    Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo

    Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
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  • Donald Y.M. Leung
    Correspondence
    Reprint requests: Donald Y. M. Leung, MD, PhD, National Jewish Medical and Research Center, 1400 Jackson Street, Room K926i, Denver, CO 80206.
    Affiliations
    Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo

    Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
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      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 β-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 TH2 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 TH2 cytokines, which inhibit keratinocyte mobilization of HBD-3.

      Key words

      Abbreviations used:

      AD (Atopic dermatitis), DAPI (4′-6-Diamidino-2-phenylindole, dihydrochloride), HBD-3 (Human β-defensin-3), KGM (Keratinocyte Growth Medium), MRSA (Methicillin-resistant Staphylococcus aureus)
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      References

      1. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.
        Lancet. 1998; 351: 1225-1232
        • Leung D.Y.
        • Bieber T.
        Atopic dermatitis.
        Lancet. 2003; 361: 151-160
        • Leyden J.J.
        • Marples R.R.
        • Kligman A.M.
        Staphylococcus aureus in the lesions of atopic dermatitis.
        Br J Dermatol. 1974; 90: 525-530
        • McGirt L.Y.
        • Beck L.A.
        Innate immune defects in atopic dermatitis.
        J Allergy Clin Immunol. 2006; 118: 202-208
        • Howell M.D.
        • Wollenberg A.
        • Gallo R.L.
        • Flaig M.
        • Streib J.E.
        • Wong C.
        • et al.
        Cathelicidin deficiency predisposes to eczema herpeticum.
        J Allergy Clin Immunol. 2006; 117: 836-841
        • Chung H.-J.
        • Jeon H.-S.
        • Sung H.
        • Kim M.-N.
        Epidemiologic characteristics of methicillin-resistant Staphylococcus aureus isolated 1 from eczematous lesion of atopic dermatitis children.
        J Clin Microbiol. 2008; 46: 991-995
        • Blanpain C.
        • Fuchs E.
        Epidermal stem cells of the skin.
        Annu Rev Cell Dev Biol. 2006; 22: 339-373
        • Elias P.
        • Ahn S.
        • Brown B.
        • Crumrine D.
        • Feingold K.R.
        Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms.
        J Invest Dermatol. 2002; 119: 1269-1274
        • Elias P.M.
        • Ahn S.K.
        • Denda M.
        • Brown B.E.
        • Crumrine D.
        • Kimutai L.K.
        • et al.
        Modulations in epidermal calcium regulate the expression of differentiation-specific markers.
        J Invest Dermatol. 2002; 119: 1128-1136
        • Liu A.Y.
        • Destoumieux D.
        • Wong A.V.
        • Park C.H.
        • Valore E.V.
        • Liu L.
        • et al.
        Human beta-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation.
        J Invest Dermatol. 2002; 118: 275-281
        • Nomura I.
        • Goleva E.
        • Howell M.D.
        • Hamid Q.A.
        • Ong P.Y.
        • Hall C.F.
        • et al.
        Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
        J Immunol. 2003; 171: 3262-3269
        • Howell M.D.
        • Gallo R.L.
        • Boguniewicz M.
        • Jones J.F.
        • Wong C.
        • Streib J.E.
        • et al.
        Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus.
        Immunity. 2006; 24: 341-348
        • Kisich K.O.
        • Howell M.D.
        • Boguniewicz M.
        • Heizer H.R.
        • Watson N.U.
        • Leung D.Y.
        The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3.
        J Invest Dermatol. 2007; 127: 2368-2380
        • Hanifin J.M.
        • Rajka G.
        Diagnostic features of atopic dermatitis.
        Acta Derm Venereol. 1980; 92: 44-49
        • Gross G.N.
        • Rehm S.R.
        • Toews G.B.
        • Hart D.A.
        • Pierce A.K.
        Lung clearance of Staphylococcus aureus strains with differing protein A content: protein A effect on in vivo clearance.
        Infect Immun. 1978; 21: 7-9
      2. Kisich KO, Higgins M, Diamond G, Heifets L. Tumor necrosis factor alpha stimulates killing of Mycobacterium tuberculosis by human neutrophils. Infect Immun 2992;70:4591-9.

        • Hamid Q.
        • Boguniewicz M.
        • Leung D.Y.
        Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis.
        J Clin Invest. 1994; 94: 870-876
        • Hamid Q.
        • Naseer T.
        • Minshall E.M.
        • Song Y.L.
        • Boguniewicz M.
        • Leung D.Y.
        In vivo expression of IL-12 and IL-13 in atopic dermatitis.
        J Allergy Clin Immunol. 1996; 98: 225-231
        • Howell M.D.
        • Boguniewicz M.
        • Pastore S.
        • Novak N.
        • Bieber T.
        • Girolomoni G.
        • et al.
        Mechanism of HBD-3 deficiency in atopic dermatitis.
        Clin Immunol. 2006; 121: 332-338
        • Leung D.Y.
        Atopic dermatitis: immunobiology and treatment with immune modulators.
        Clin Exp Immunol. 1997; 107: 25-30
        • Kluytmans J.
        • van Belkum A.
        • Verbrugh H.
        Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks.
        Clin Microbiol Rev. 1997; 10: 505-520
        • Fridkin S.K.
        • Hageman J.C.
        • Morrison M.
        • Sanza L.T.
        • Como-Sabetti K.
        • Jernigan J.A.
        • et al.
        Methicillin-resistant Staphylococcus aureus disease in three communities.
        N Engl J Med. 2005; 352: 1436-1444
        • Moser C.
        • Weiner D.J.
        • Lysenko E.
        • Bals R.
        • Weiser J.N.
        • Wilson J.M.
        beta-Defensin 1 contributes to pulmonary innate immunity in mice.
        Infect Immun. 2002; 70: 3068-3072
        • Bevins C.L.
        The Paneth cell and the innate immune response.
        Curr Opin Gastroenterol. 2004; 20: 572-580
        • Fehrenbach K.
        • Port F.
        • Grochowy G.
        • Kalis C.
        • Bessler W.
        • Galanos C.
        • et al.
        Stimulation of mast cells via FcepsilonR1 and TLR2: the type of ligand determines the outcome.
        Mol Immunol. 2007; 44: 2087-2094
        • Silliman C.C.
        • Elzi D.J.
        • Ambruso D.R.
        • Musters R.J.
        • Hamiel C.
        • Harbeck R.J.
        • et al.
        Lysophosphatidylcholines prime the NADPH oxidase and stimulate multiple neutrophil functions through changes in cytosolic calcium.
        J Leukoc Biol. 2003; 73: 511-524
        • TranVan Nhieu G.
        • Clair C.
        • Grompone G.
        • Sansonetti P.
        Calcium signalling during cell interactions with bacterial pathogens.
        Biol Cell. 2004; 96: 93-101
        • Albanesi C.
        • Fairchild H.R.
        • Madonna S.
        • Scarponi C.
        • De Pità O.
        • Leung D.Y.
        • et al.
        IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3.
        J Immunol. 2007; 179: 984-992
        • Stalder J.F.
        • Fleury M.
        • Sourisse M.
        • Rostin M.
        • Pheline F.
        • Litoux P.
        Local steroid therapy and bacterial skin flora in atopic dermatitis.
        Br J Dermatol. 1994; 131: 536-540
        • Remitz A.
        • Kyllonen H.
        • Granlund H.
        • Reitamo S.
        Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions.
        J Allergy Clin Immunol. 2001; 107: 196-197