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Innate immunity

ADAM17 — gatekeeper of the skin barrier

Nature Reviews Immunology volume 12, pages 154–155 (2012)Cite this article

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Mice with a targeted deletion of Adam17 in basal keratinocytes (Adam17Δep mice) developed a progressive atopic dermatitis-like inflammatory skin disease. The disease was associated with a marked accumulation of macrophages and mast cells in the skin and increased levels of the alarmins thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33) in the skin and blood. Adam17Δep mice also had high concentrations of T helper 2 (TH2)-type and TH17-type cytokines and low concentrations of TH1-type cytokines, which are characteristics that are typical of atopic diseases. Consistent with this polarized cytokine response, analyses of skin-draining lymph nodes from diseased mice showed increased populations of activated lymphocytes, including TH2 cells, TH17 cells and IL-17-producing γδ T cells. The expansion of myeloid cell populations was in keeping with the presence of high concentrations of granulocyte colony-stimulating factor (G-CSF) and splenomegaly.

The authors noted that the disease in Adam17Δep mice was similar to that which occurs in mice with an epidermal deletion of Notch1 and Notch2. So they tested whether ADAM17-deficient skin had a defect in Notch signalling. Indeed, Adam17−/− keratinocytes failed to produce the cleaved active Notch fragment Notch intracellular domain (NICD) after ligand-independent Notch activation, although ligand-dependent Notch activation remained intact. Interestingly, based on analyses of published microarray data, a Notch signalling defect may also occur in patients with atopic skin disease.

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ORIGINAL RESEARCH PAPER

  1. Murthy, A. et al. Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis. Immunity 36, 105–119 (2012)Article

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  1. Lucy Bird
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Bird, L. ADAM17 — gatekeeper of the skin barrier. Nat Rev Immunol 12, 154–155 (2012). https://doi.org/10.1038/nri3178

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