Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand–dependent terminal keratinocyte differentiation

• DOI: 10.1084/jem.20112258
• Publication Date: 2012-05-08T06:55:26Z
• Authors: Claus-Werner Franzke; Cristina Cobzaru; Antigoni Triantaf...; Stefanie Löffek; Keisuke Horiuchi; David W. Threadgill; Thomas Kurz; Nico van Rooijen; Leena Bruckner-Tu...; Carl P. Blobel
• Keywords: Proinflammatory cytokine; Transepidermal water loss

ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, TNF, from the cell surface, thus regulating responses to tissue injury inflammation. However, little currently known about its role in skin homeostasis. We show that mice lacking keratinocytes (A17(ΔKC)) have a normal barrier architecture at birth but develop pronounced defects integrity soon after chronic dermatitis adults. The dysregulated expression of differentiation proteins becomes evident 2 d birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation proinflammatory cytokine IL-36α, inflammatory immune infiltration. Activation EGFR was strongly A17(ΔKC) skin, topical treatment with recombinant TGF-α significantly improved TGM activity decreased Finally, we (Egfr(ΔKC)) closely resembled mice. Collectively, these results identify previously unappreciated critical ADAM17-EGFR signaling axis maintaining homeostasis postnatal suggest this pathway could represent good target for defects.