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. 2012 May;132(5):1513-6.
doi: 10.1038/jid.2011.462. Epub 2012 Mar 1.

Genetic requirement for ADAM10 in severe Staphylococcus aureus skin infection

Naoko Inoshima, Yang Wang, Juliane Bubeck Wardenburg

Genetic requirement for ADAM10 in severe Staphylococcus aureus skin infection

Naoko Inoshima et al. J Invest Dermatol. 2012 May.
No abstract available

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Conflict of interest statement

CONFLICT OF INTEREST

JBW has a financial relationship with Novartis associated with patents owned by The University of Chicago.

Figures

Fig. 1
Fig. 1
ADAM10 mediates α-hemolysin dependent epithelial injury. (a) Epidermal expression of ADAM10 visualized by anti-mouse ADAM10 immunohistochemical staining of tissues derived from ADAM10−/− mice in which topical treatment with tamoxifen (TAM, dissolved in ethanol, 1 mg per mouse per day for 5 days, applied to a 1 cm2 area) induces loss of ADAM10 expression through Cre recombinase-mediated excision of ADAM10loxP alleles or control mice treated with ethanol alone. (b) Dermonecrosis area recorded from control mice that received topical treatment with vehicle alone (n = 13) or TAM (n = 8), or ADAM10−/− mice treated with TAM (n = 13) followed by subcutaneous infection at the site of vehicle or TAM application with 3 × 107 S. aureus USA300/LAC, where * denotes P < 0.001. (c) Image of mice treated as described in (b) and (d). (d) Abscess area recorded from mice detailed in (b) where + denotes P < 0.05. Area in (b) and (d) was calculated based on the formula A = [π/2] × length × width where error bars represent SEM. All animal studies were reviewed, approved, and supervised by the Institutional Animal Care and Use Committee at the University of Chicago. (e) Cell-associated metalloprotease activity measured in A431 keratinocytes following treatment with 10 Rg ml−1 (300 nM) active Hla or the non-toxigenic mutant HlaH35L at the time points indicated. Activity was quantified by detection of the product derived from cleavage of the fluorogenic peptide substrate Mca-PLAQAV-Dpa-RSSSR-NH2 (10 RM, R&D Systems, Minnesota) diluted in 25 mM Tris, pH 8.0. (f) Immunoblot analysis of full-length (Fl) E-cadherin and accumulation of the C-terminal cleavage fragment (Ctf) following treatment of A431 cells with controls DMSO and ionomycin compared to 10 Rg ml−1 HlaH35L or Hla over the time course indicated. (g) Electrical cell substrate impedance sensing (ECIS, Applied Biophysics, New York) recordings of A431 monolayers treated with PBS (black), the HlaH35L mutant (10 Rg ml−1, red), or active Hla (10 Rg ml−1, blue). (h) E-cadherin (green) immunofluorescence microscopy analysis of tissue from control or ADAM10−/− mice 24 hours following infection with 3 × 107 S. aureus delivered by subcutaneous route. Nuclei (blue) are stained with the fluorescent DNA stain DAPI. (i) Hematoxylin and eosin staining of tissues from mice treated as described in (h), shown at 4X (upper) with a 20X image of the highlighted area (lower). The site of infection and inflammatory cell recruitment is marked by yellow arrows. Scale bars in (a) = 50 μm, (h) = 10 μm, (i) = 100 μm.
Fig. 2
Fig. 2
An ADAM10 inhibitor protects against Hla-induced injury. (a) Dermonecrosis area recorded from wild-type mice that received a five-day course of once-daily intraperitoneal injection with vehicle alone (DMSO) or the ADAM10 inhibitor GI254023X (200 mg per kg per day, Okeanos, China), followed by subcutaneous infection with 3 × 107 S. aureus USA300/LAC (n = 10 mice per group). (b) Dermonecrosis area recorded from wild-type mice that received a five-day course of once-daily topical application with vehicle alone (DMSO) or the ADAM10 inhibitor GI254023X (100 mg per kg per day), followed by subcutaneous infection with 3 × 107 S. aureus USA300/LAC (n = 10 mice per group), where + denotes P < 0.05 and * denotes P < 0.001 in (a) and (b). (c) Immunoblot analysis of full-length E-cadherin (Fl) and accumulation of the C-terminal cleavage fragment (Ctf) following pre-treatment of A431 cells with DMSO or GI254023X, then exposed to 10 Rg ml−1 Hla for the time periods indicated. (d) Electrical cell substrate impedance sensing (ECIS) recordings of A431 monolayers treated with PBS (black), or Hla (10 Rg ml−1) following pre-treatment with control DMSO (blue) or GI254023X (20 Rg ml−1, red).
See this image and copyright information in PMC

References

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