Serine protease signaling of epidermal permeability barrier homeostasis

Autor(en): Hachem, Jean-Pierre
Houben, Evi
Crumrine, Debra
Man, Mao-Quiang
Schurer, Nanna 
Roelandt, Truus
Choi, Eung H.
Uchida, Yoshikazu
Brown, Barbara E.
Feingold, Kenneth R.
Elias, Peter M.
Stichwörter: CALCIUM-METABOLISM; CERAMIDE SYNTHESIS; CHILDHOOD ATOPIC-DERMATITIS; Dermatology; KERATINOCYTE DIFFERENTIATION; LAMELLAR BODIES; MOLECULAR-CLONING; MURINE EPIDERMIS; PROTEINASE-ACTIVATED RECEPTOR-2; STRATUM-CORNEUM; TISSUE DISTRIBUTION
Erscheinungsdatum: 2006
Herausgeber: NATURE PUBLISHING GROUP
Journal: JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volumen: 126
Ausgabe: 9
Startseite: 2074
Seitenende: 2086
Zusammenfassung: 
Evidence is growing that protease-activated receptor-2 (PAR-2) plays a key role in epithelial inflammation. We hypothesized here that PAR-2 plays a central role in epidermal permeability barrier homeostasis by mediating signaling from serine proteases (SP) in the stratum corneum (SC). Since the SC contains tryptic- and chymotryptic-like activity, we assessed the influence of SP activation/inhibition on barrier function. Acute barrier disruption increases SP activity and blockade by topical SP inhibitors (SPI) accelerates barrier recovery after acute abrogation. This improvement in barrier function is due to accelerated lamellar body (LB) secretion. Since tryptic SP signal certain downstream responses through PAR-2, we assessed its potential role in mediating the negative effects of SP on permeability barrier. Firstly, PAR-2 is expressed in the outer nucleated layers of the epidermis and most specifically under basal condition to the lipid raft (LR) domains. Secondly, tape stripping-induced barrier abrogation provokes PAR-2 activation, as shown by receptor internalization (i.e. receptor movement from LR to cytolpasmic domains). Thirdly, topical applications of PAR-2 agonist peptide, SLIGRL, delay permeability barrier recovery and inhibit LB secretion, while, conversely, PAR-2 knockout mice display accelerated barrier recovery kinetics and enhanced LB secretion, paralleled by increased LR formation and caveolin-1 expression. These results demonstrate first, the importance of SP/SPI balance for normal permeability barrier homeostasis, and second, they identify PAR-2 as a novel signaling mechanism of permeability barrier, that is, of response linked to LB secretion.
ISSN: 0022202X
DOI: 10.1038/sj.jid.5700351

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