PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin

Simona Frateschi, Eric Camerer, Giovanna Crisante, Sarah Rieser, Mathieu Membrez, Roch-Philippe Charles, Friedrich Beermann, Jean-Christophe Stehle, Bernadette Breiden, Konrad Sandhoff, Samuel Rotman, Marek Haftek, Anne Wilson, Stephan Ryser, Martin Steinhoff, Shaun R. Coughlin and Edith Hummler ()
Additional contact information
Simona Frateschi: University of Lausanne
Eric Camerer: Cardiovascular Research Institute, University of California
Giovanna Crisante: University of Lausanne
Sarah Rieser: University of Lausanne
Mathieu Membrez: University of Lausanne
Roch-Philippe Charles: University of Lausanne
Friedrich Beermann: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Jean-Christophe Stehle: University of Lausanne
Bernadette Breiden: LIMES, Membrane Biology & Lipid Biochemistry Unit c/o Kekulé-Institut für Organische Chemie und Biochemie der Universität, University of Bonn
Konrad Sandhoff: LIMES, Membrane Biology & Lipid Biochemistry Unit c/o Kekulé-Institut für Organische Chemie und Biochemie der Universität, University of Bonn
Samuel Rotman: University of Lausanne
Marek Haftek: University of Lyon, EA4169: Normal and Pathological Functions of the Skin Barrier
Anne Wilson: Ludwig Institute for Cancer Research, University of Lausanne
Stephan Ryser: Laboratory of Cutaneous Biology, CHUV, University of Lausanne
Martin Steinhoff: University of California
Shaun R. Coughlin: Cardiovascular Research Institute, University of California
Edith Hummler: University of Lausanne

Nature Communications, 2011, vol. 2, issue 1, 1-11

Abstract: Abstract Altered serine protease activity is associated with skin disorders in humans and in mice. The serine protease channel-activating protease-1 (CAP1; also termed protease serine S1 family member 8 (Prss8)) is important for epidermal homeostasis and is thus indispensable for postnatal survival in mice, but its roles and effectors in skin pathology are poorly defined. In this paper, we report that transgenic expression in mouse skin of either CAP1/Prss8 (K14-CAP1/Prss8) or protease-activated receptor-2 (PAR2; Grhl3PAR2/+), one candidate downstream target, causes epidermal hyperplasia, ichthyosis and itching. K14-CAP1/Prss8 ectopic expression impairs epidermal barrier function and causes skin inflammation characterized by an increase in thymic stromal lymphopoietin levels and immune cell infiltrations. Strikingly, both gross and functional K14-CAP1/Prss8-induced phenotypes are completely negated when superimposed on a PAR2-null background, establishing PAR2 as a pivotal mediator of pathogenesis. Our data provide genetic evidence for PAR2 as a downstream effector of CAP1/Prss8 in a signalling cascade that may provide novel therapeutic targets for ichthyoses, pruritus and inflammatory skin diseases.

Date: 2011
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DOI: 10.1038/ncomms1162

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