title: Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis.
abstract: Epithelial cells of mucosal tissues provide a barrier against environmental stress, and keratinocytes are key decision makers for immune cell function in the skin. Currently, epithelial signaling networks that instruct barrier immunity remain uncharacterized. Here we have shown that keratinocyte-specific deletion of a disintegrin and metalloproteinase 17 (Adam17) triggers T helper 2 and/or T helper 17 (Th2 and/or Th17) cell-driven atopic dermatitis and myeloproliferative disease. In vivo and in vitro deficiency of ADAM17 dampened Notch signaling, increasing production of the Th2 cell-polarizing cytokine TSLP and myeloid growth factor G-CSF. Ligand-independent Notch activation was identified as a regulator of AP-1 transcriptional activity, with Notch antagonizing c-Fos recruitment to the promoters of Tslp and Csf3 (G-CSF). Further, skin inflammation was rescued and myeloproliferation ameliorated by delivery of active Notch to Adam17(-)(/-) epidermis. Our findings uncover an essential role of ADAM17 in the adult epidermis, demonstrating a gatekeeper function of the ADAM17-Notch-c-Fos triad in barrier immunity.
authors.affiliation: Ontario Cancer Institute, Toronto, Canada.
authors.forename: Aditya
authors.initials: A
authors.lastname: Murthy
authors.forename: Yang Washington
authors.initials: YW
authors.lastname: Shao
authors.forename: Swami R
authors.initials: SR
authors.lastname: Narala
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology* / Q000276:immunology*; D017353:Gene Deletion; D042381:Granulocyte Precursor Cells / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051880:Receptors, Notch / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D051880:Receptors, Notch; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse