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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

Phenotype of K14-CAP1/Prss8 transgenic mice.(a) Macroscopic appearance of transgenic mice and littermate controls at 1 week (1 wk), 2 weeks (2 wk) and 5 months (5 mo) of age. (b) Quantification of the number (Nb.) of hair follicles in transgenic versus control skin. n=3 mice per genotype, *P<0.05. (c) Haematoxylin and eosin analyses of 2-day (2 d)-, 2-week (14 d)- and 5-month (5 mo)-old K14-CAP1/Prss8 mice compared with wild-type littermates. White bars indicate the thickness of the epidermis. Scale bars indicate 20 μm. n=3 mice per genotype. (d) Quantification of the number of Ki67-positive cells in the epidermis of 2-week-old animals. (e) Quantification of the number (Nb.) of cells undergoing apoptosis in the epidermis of K14-CAP1/Prss8 versus wild-type littermates (n=3 mice per genotype, NS: not significant). (f) Body weight measurements of 2-week-old male (M) and female (F) transgenic mice and littermate controls, *P<0.05. (g) Transepidermal water loss (TEWL) measurements of male and female transgenic mice. n≥4 animals per group, **P<0.01. (h) Survival curves of K14-CAP1/Prss8 versus wild-type littermates. All data are presented as mean±s.e.m.
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f2: Phenotype of K14-CAP1/Prss8 transgenic mice.(a) Macroscopic appearance of transgenic mice and littermate controls at 1 week (1 wk), 2 weeks (2 wk) and 5 months (5 mo) of age. (b) Quantification of the number (Nb.) of hair follicles in transgenic versus control skin. n=3 mice per genotype, *P<0.05. (c) Haematoxylin and eosin analyses of 2-day (2 d)-, 2-week (14 d)- and 5-month (5 mo)-old K14-CAP1/Prss8 mice compared with wild-type littermates. White bars indicate the thickness of the epidermis. Scale bars indicate 20 μm. n=3 mice per genotype. (d) Quantification of the number of Ki67-positive cells in the epidermis of 2-week-old animals. (e) Quantification of the number (Nb.) of cells undergoing apoptosis in the epidermis of K14-CAP1/Prss8 versus wild-type littermates (n=3 mice per genotype, NS: not significant). (f) Body weight measurements of 2-week-old male (M) and female (F) transgenic mice and littermate controls, *P<0.05. (g) Transepidermal water loss (TEWL) measurements of male and female transgenic mice. n≥4 animals per group, **P<0.01. (h) Survival curves of K14-CAP1/Prss8 versus wild-type littermates. All data are presented as mean±s.e.m.

Mentions: K14-CAP1/Prss8 transgenic mice were easily discernible from their control littermates just a few days after birth by their scaly skin (ichthyosis), which progressed with age and was evident most prominently in the ventral-abdominal region and the tail (line 2, Fig. 2a, line 1; Supplementary Fig. S1b). Both transgenic lines manifested ichthyosis with 100% penetrance, as well as abnormal hair growth (hypotrichosis) relative to littermate controls (Fig. 2b). No histopathological abnormalities were observed in other organs, such as thymus, tongue, oesophagus, heart, liver, lung and spleen (Supplementary Fig. S2). Histological analysis revealed epidermal hyperplasia (acanthosis) in transgenic mice from as early as 2 days of age (Fig. 2c; Supplementary Fig. S1c) associated with enhanced proliferation of keratinocytes, as evidenced by a threefold increase in the number of Ki67-positive cells in the stratum basale (Fig. 2d), without an accompanying change in the number of apoptotic cells in the epidermis (Fig. 2e). In addition to epidermal hyperplasia, the dermis of K14-CAP1/Prss8 transgenic mice was more cellular with a notable increase in the number of haematoxylin-stained nuclei (Fig. 2c).


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)

Phenotype of K14-CAP1/Prss8 transgenic mice.(a) Macroscopic appearance of transgenic mice and littermate controls at 1 week (1 wk), 2 weeks (2 wk) and 5 months (5 mo) of age. (b) Quantification of the number (Nb.) of hair follicles in transgenic versus control skin. n=3 mice per genotype, *P<0.05. (c) Haematoxylin and eosin analyses of 2-day (2 d)-, 2-week (14 d)- and 5-month (5 mo)-old K14-CAP1/Prss8 mice compared with wild-type littermates. White bars indicate the thickness of the epidermis. Scale bars indicate 20 μm. n=3 mice per genotype. (d) Quantification of the number of Ki67-positive cells in the epidermis of 2-week-old animals. (e) Quantification of the number (Nb.) of cells undergoing apoptosis in the epidermis of K14-CAP1/Prss8 versus wild-type littermates (n=3 mice per genotype, NS: not significant). (f) Body weight measurements of 2-week-old male (M) and female (F) transgenic mice and littermate controls, *P<0.05. (g) Transepidermal water loss (TEWL) measurements of male and female transgenic mice. n≥4 animals per group, **P<0.01. (h) Survival curves of K14-CAP1/Prss8 versus wild-type littermates. All data are presented as mean±s.e.m.
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Related In: Results  -  Collection

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f2: Phenotype of K14-CAP1/Prss8 transgenic mice.(a) Macroscopic appearance of transgenic mice and littermate controls at 1 week (1 wk), 2 weeks (2 wk) and 5 months (5 mo) of age. (b) Quantification of the number (Nb.) of hair follicles in transgenic versus control skin. n=3 mice per genotype, *P<0.05. (c) Haematoxylin and eosin analyses of 2-day (2 d)-, 2-week (14 d)- and 5-month (5 mo)-old K14-CAP1/Prss8 mice compared with wild-type littermates. White bars indicate the thickness of the epidermis. Scale bars indicate 20 μm. n=3 mice per genotype. (d) Quantification of the number of Ki67-positive cells in the epidermis of 2-week-old animals. (e) Quantification of the number (Nb.) of cells undergoing apoptosis in the epidermis of K14-CAP1/Prss8 versus wild-type littermates (n=3 mice per genotype, NS: not significant). (f) Body weight measurements of 2-week-old male (M) and female (F) transgenic mice and littermate controls, *P<0.05. (g) Transepidermal water loss (TEWL) measurements of male and female transgenic mice. n≥4 animals per group, **P<0.01. (h) Survival curves of K14-CAP1/Prss8 versus wild-type littermates. All data are presented as mean±s.e.m.
Mentions: K14-CAP1/Prss8 transgenic mice were easily discernible from their control littermates just a few days after birth by their scaly skin (ichthyosis), which progressed with age and was evident most prominently in the ventral-abdominal region and the tail (line 2, Fig. 2a, line 1; Supplementary Fig. S1b). Both transgenic lines manifested ichthyosis with 100% penetrance, as well as abnormal hair growth (hypotrichosis) relative to littermate controls (Fig. 2b). No histopathological abnormalities were observed in other organs, such as thymus, tongue, oesophagus, heart, liver, lung and spleen (Supplementary Fig. S2). Histological analysis revealed epidermal hyperplasia (acanthosis) in transgenic mice from as early as 2 days of age (Fig. 2c; Supplementary Fig. S1c) associated with enhanced proliferation of keratinocytes, as evidenced by a threefold increase in the number of Ki67-positive cells in the stratum basale (Fig. 2d), without an accompanying change in the number of apoptotic cells in the epidermis (Fig. 2e). In addition to epidermal hyperplasia, the dermis of K14-CAP1/Prss8 transgenic mice was more cellular with a notable increase in the number of haematoxylin-stained nuclei (Fig. 2c).

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