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

Frateschi S, Camerer E, Crisante G, Rieser S, Membrez M, Charles RP, Beermann F, Stehle JC, Breiden B, Sandhoff K, Rotman S, Haftek M, Wilson A, Ryser S, Steinhoff M, Coughlin SR, Hummler E - Nat Commun (2011)

Bottom Line: 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1005, Switzerland.

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; Grhl3(PAR2/+)), 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- 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.

No MeSH data available.


Related in: MedlinePlus

Localization of CAP1/Prss8 and PAR2 in human epidermis.Immunohistochemistry of CAP1/Prss8 and PAR2, both in green, in human skin sections. Nuclei are counterstained with DAPI (blue). Bottom panel: parallel sections in which primary antibodies were omitted (negative control; No 1 Ab). The pictures are representative of biopsies analysed from two adult subjects with atopic dermatitis, five with acute dermatitis, three with chronic dermatitis and from four healthy controls. Dashed white lines represent epidermal/dermal junction. Scale bars represent 10 μm. BF: bright field.
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f7: Localization of CAP1/Prss8 and PAR2 in human epidermis.Immunohistochemistry of CAP1/Prss8 and PAR2, both in green, in human skin sections. Nuclei are counterstained with DAPI (blue). Bottom panel: parallel sections in which primary antibodies were omitted (negative control; No 1 Ab). The pictures are representative of biopsies analysed from two adult subjects with atopic dermatitis, five with acute dermatitis, three with chronic dermatitis and from four healthy controls. Dashed white lines represent epidermal/dermal junction. Scale bars represent 10 μm. BF: bright field.

Mentions: CAP1/Prss8 immunodetection on skin cross-sections from four healthy controls and from five acute, two atopic and three chronic dermatitis patients showed defined localization of CAP1/Prss8 in the granular layer of the human epidermis (Fig. 7) similar to CAP1/Prss8 expression in murine skin8. In healthy controls and acute dermatitis patients, CAP1/Prss8 was localized both intracellularly and at the plasma membrane. In patients with chronic and atopic dermatitis, CAP1/Prss8 appeared to be predominantly expressed at the plasma membrane. PAR2 expression was seen in suprabasal keratinocytes in the same samples and appeared to be more extensive in chronic and atopic dermatitis patients, following hyperplasia. It is thus conceivable that differential expression of CAP1/Prss8 and/or PAR2 in diseased versus healthy skin may contribute to the pathogenesis of these disorders.


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

Frateschi S, Camerer E, Crisante G, Rieser S, Membrez M, Charles RP, Beermann F, Stehle JC, Breiden B, Sandhoff K, Rotman S, Haftek M, Wilson A, Ryser S, Steinhoff M, Coughlin SR, Hummler E - Nat Commun (2011)

Localization of CAP1/Prss8 and PAR2 in human epidermis.Immunohistochemistry of CAP1/Prss8 and PAR2, both in green, in human skin sections. Nuclei are counterstained with DAPI (blue). Bottom panel: parallel sections in which primary antibodies were omitted (negative control; No 1 Ab). The pictures are representative of biopsies analysed from two adult subjects with atopic dermatitis, five with acute dermatitis, three with chronic dermatitis and from four healthy controls. Dashed white lines represent epidermal/dermal junction. Scale bars represent 10 μm. BF: bright field.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105307&req=5

f7: Localization of CAP1/Prss8 and PAR2 in human epidermis.Immunohistochemistry of CAP1/Prss8 and PAR2, both in green, in human skin sections. Nuclei are counterstained with DAPI (blue). Bottom panel: parallel sections in which primary antibodies were omitted (negative control; No 1 Ab). The pictures are representative of biopsies analysed from two adult subjects with atopic dermatitis, five with acute dermatitis, three with chronic dermatitis and from four healthy controls. Dashed white lines represent epidermal/dermal junction. Scale bars represent 10 μm. BF: bright field.
Mentions: CAP1/Prss8 immunodetection on skin cross-sections from four healthy controls and from five acute, two atopic and three chronic dermatitis patients showed defined localization of CAP1/Prss8 in the granular layer of the human epidermis (Fig. 7) similar to CAP1/Prss8 expression in murine skin8. In healthy controls and acute dermatitis patients, CAP1/Prss8 was localized both intracellularly and at the plasma membrane. In patients with chronic and atopic dermatitis, CAP1/Prss8 appeared to be predominantly expressed at the plasma membrane. PAR2 expression was seen in suprabasal keratinocytes in the same samples and appeared to be more extensive in chronic and atopic dermatitis patients, following hyperplasia. It is thus conceivable that differential expression of CAP1/Prss8 and/or PAR2 in diseased versus healthy skin may contribute to the pathogenesis of these disorders.

Bottom Line: 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1005, Switzerland.

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; Grhl3(PAR2/+)), 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- 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.

No MeSH data available.


Related in: MedlinePlus