Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor
Ole E. Sørensen, Dharma R. Thapa, K. Markus Roupé, Erika V. Valore, Ulf Sjöbring, Alice A. Roberts, Artur Schmidtchen, Tomas Ganz
Ole E. Sørensen, Dharma R. Thapa, K. Markus Roupé, Erika V. Valore, Ulf Sjöbring, Alice A. Roberts, Artur Schmidtchen, Tomas Ganz
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Research Article Dermatology

Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor

Abstract

We found that sterile wounding of human skin induced epidermal expression of the antimicrobial (poly)peptides human β-defensin–3, neutrophil gelatinase–associated lipocalin, and secretory leukocyte protease inhibitor through activation of the epidermal growth factor receptor. After skin wounding, the receptor was activated by heparin-binding epidermal growth factor that was released by a metalloprotease-dependent mechanism. Activation of the epidermal growth factor receptor generated antimicrobial concentrations of human β-defensin–3 and increased the activity of organotypic epidermal cultures against Staphylococcus aureus. These data demonstrate that sterile wounding initiates an innate immune response that increases resistance to overt infection and microbial colonization.

Authors

Ole E. Sørensen, Dharma R. Thapa, K. Markus Roupé, Erika V. Valore, Ulf Sjöbring, Alice A. Roberts, Artur Schmidtchen, Tomas Ganz

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Figure 7

Identification of EGFR ligand responsible for hBD-3 induction in wounded skin.

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Identification of EGFR ligand responsible for hBD-3 induction in wounded...
(A) Skin slices were incubated with the metalloprotease inhibitor TAPI-1 or with the DMSO vehicle used to dissolve the TAPI-1. Expression of hBD-3 was analyzed by real-time qRT-PCR on days 0 and 4. The expression of hBD-3 at day 4 was set to 1. TAPI-1 inhibited the expression of hBD-3 compared with the DMSO vehicle (n = 3, P < 0.002). Mean and standard deviation are shown. (B) Skin slices (n = 4) were incubated with control antibodies or antibodies against TGF-α and HB-EGF. The expression of RNA was analyzed by real-time qRT-PCR and normalized to G3PD as housekeeping mRNA control. The expression of hBD-3 on day 4 in the presence of control antibodies was set to 1. Due to limited access to whole skin, not all of the inhibition experiments were carried out each time. HB-EGF antibodies significantly inhibited the expression of hBD-3 compared with control antibodies (P < 0.003). Mean and standard deviation are shown. (C) Skin slices were incubated with an analog of diphtheria toxin, CRM197 (n = 3). CRM197 associates with membrane-bound HB-EGF and prevents its proteolytic liberation. The expression of mRNA was analyzed by real-time qRT-PCR and normalized to the G3PD as housekeeping mRNA control. The expression of hBD-3 on day 4 was set to 1. CRM197 significantly inhibited the expression of hBD-3 compared with control antibodies (P < 0.03). Mean and standard deviation are shown.