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

The Journal of Experimental Medicine
Claus-Werner FranzkeCarl P Blobel

Abstract

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

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Methods Mentioned

BETA
biopsies
PCR
Flow cytometry
ELISA
transgenic
electrophoresis
protein
ELISAs

Software Mentioned

ImageJ
1D Advanced
GeneSpring GX
GraphPad
Prism
BIO
Kaluza
AxioVision

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