Epidermal ADAM17 provides barrier immunity and prevents myeloproliferative disease by regulating Notch-AP1 interaction (166.7)

Abstract

Abstract Epithelial cells are the major component of mucosal tissues such as the skin, gut and lungs. They are critical barriers against environmental stress factors which induce significant immunopathology. Keratinocytes in the skin may act as key decision-makers of immune cell function by directing local adaptive immune responses and hematopoietic development, however mechanisms driving epithelial:immune crosstalk are incompletely understood. The cell surface sheddase A Disintegrin and Metalloproteinase 17 (ADAM17) cleaves numerous proteins with key roles in development, stress response and inflammation. Here we show that loss of epidermal Adam17 leads to severe atopic dermatitis and myeloproliferative disease. ADAM17 deficiency in keratinocytes enhanced AP1 signaling, increasing the production of epithelial cytokines (e.g. TSLP, IL-33) to drive Th2-polarized lymphocyte activation. We also observed the release of myeloid growth factors (e.g. G-CSF), causal to myeloproliferative disease in these mice. Next, we identified that ADAM17 promotes ligand-independent Notch activation in keratinocytes, revealing a novel mechanism of Notch-AP1 interaction that abrogates stress signaling. Notably, ectopic Notch activation in the epidermis of ADAM17 deficient mice rescued local inflammation and myeloproliferation. Thus Notch activation by ADAM17 in keratinocytes antagonizes AP1-induced inflammation, thereby establishing a mechanism of epithelial:immune crosstalk.