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Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

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Reversal of psoriasis-like skin disease in PPAR β/δ mice by PPAR β/δ antagonists.Skin disease was induced by systemic oral administration of the PPAR β/δ agonist GW501516. (Control mice received standard chow). Subsequently, GW501516 dose was lowered to allow maintenance of phenotype as described in the text and mice were treated twice daily with either vehicle only (GW501516 group) or antagonist-containing ointments, as indicated. A. Reversal of epidermal hyperplasia, performed as described in the legend for figure 5. Horizontal bar represents 5 µm. B. Reduction of T cell infiltration. Skin samples of the treated skin regions were processed and stained for FACS analysis as described in Methods. Scatter plots shown on left show representative data, column diagrams on right show quantification of FACS data in n = 4 mice per group. The scatter plot shown at the bottom indicates the lympocyte gate used for quantification of CD4/CD8 cells, as previously described [21]. C. Quantification of target genes previously been shown to be induced in PPAR β/δ transgenic mice by qPCR, as detailed in Methods. * p<0.05 in a two-sided independent t-test.
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pone-0037097-g006: Reversal of psoriasis-like skin disease in PPAR β/δ mice by PPAR β/δ antagonists.Skin disease was induced by systemic oral administration of the PPAR β/δ agonist GW501516. (Control mice received standard chow). Subsequently, GW501516 dose was lowered to allow maintenance of phenotype as described in the text and mice were treated twice daily with either vehicle only (GW501516 group) or antagonist-containing ointments, as indicated. A. Reversal of epidermal hyperplasia, performed as described in the legend for figure 5. Horizontal bar represents 5 µm. B. Reduction of T cell infiltration. Skin samples of the treated skin regions were processed and stained for FACS analysis as described in Methods. Scatter plots shown on left show representative data, column diagrams on right show quantification of FACS data in n = 4 mice per group. The scatter plot shown at the bottom indicates the lympocyte gate used for quantification of CD4/CD8 cells, as previously described [21]. C. Quantification of target genes previously been shown to be induced in PPAR β/δ transgenic mice by qPCR, as detailed in Methods. * p<0.05 in a two-sided independent t-test.

Mentions: We next investigated whether PPAR β/δ antagonists are able to reverse established skin disease. For this experiment, we administered the agonist GW501516 orally in order to allow twice – daily topical application of the antagonist without possible interference with drug penetration. We thus induced skin disease by oral dosing of GW501516, using a modified dosing regimen to that previously described as detailed in Methods. Three weeks after initiation of treatment with antagonists, mice were sacrificed and skin samples analysed. As shown in figure 6a, both PPAR β/δ antagonists were able to partially reverse epidermal hyperplasia. The influx of both CD4+ and CD8+ T lymphocyte subsets was also reduced, as shown in figure 6b. (cell numbers were too low to allow quantification of IL17+ T cell subsets). Finally, we also quantified expression levels of genes previously shown to be induced by PPAR β/δ in the skin [21], HB-EGF, a direct target gene of PPAR β/δ [22], as well as two strongly induced indirect target genes, IL1b and LCE3e. As shown in figure 6c, the upregulation of both HB-EGF and LCE3e was partially reversed by treatment with both PPAR β/δ antagonists, although this reached statistical significance only for LCE3e. Reversal of IL1b expression was only observed using the ointment containing GSK0660. Taken together, these data show that transdermal application of PPAR β/δ antagonists is able to reverse established psoriasis-like disease in PPAR β/δ transgenic mice.


Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Reversal of psoriasis-like skin disease in PPAR β/δ mice by PPAR β/δ antagonists.Skin disease was induced by systemic oral administration of the PPAR β/δ agonist GW501516. (Control mice received standard chow). Subsequently, GW501516 dose was lowered to allow maintenance of phenotype as described in the text and mice were treated twice daily with either vehicle only (GW501516 group) or antagonist-containing ointments, as indicated. A. Reversal of epidermal hyperplasia, performed as described in the legend for figure 5. Horizontal bar represents 5 µm. B. Reduction of T cell infiltration. Skin samples of the treated skin regions were processed and stained for FACS analysis as described in Methods. Scatter plots shown on left show representative data, column diagrams on right show quantification of FACS data in n = 4 mice per group. The scatter plot shown at the bottom indicates the lympocyte gate used for quantification of CD4/CD8 cells, as previously described [21]. C. Quantification of target genes previously been shown to be induced in PPAR β/δ transgenic mice by qPCR, as detailed in Methods. * p<0.05 in a two-sided independent t-test.
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Related In: Results  -  Collection

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pone-0037097-g006: Reversal of psoriasis-like skin disease in PPAR β/δ mice by PPAR β/δ antagonists.Skin disease was induced by systemic oral administration of the PPAR β/δ agonist GW501516. (Control mice received standard chow). Subsequently, GW501516 dose was lowered to allow maintenance of phenotype as described in the text and mice were treated twice daily with either vehicle only (GW501516 group) or antagonist-containing ointments, as indicated. A. Reversal of epidermal hyperplasia, performed as described in the legend for figure 5. Horizontal bar represents 5 µm. B. Reduction of T cell infiltration. Skin samples of the treated skin regions were processed and stained for FACS analysis as described in Methods. Scatter plots shown on left show representative data, column diagrams on right show quantification of FACS data in n = 4 mice per group. The scatter plot shown at the bottom indicates the lympocyte gate used for quantification of CD4/CD8 cells, as previously described [21]. C. Quantification of target genes previously been shown to be induced in PPAR β/δ transgenic mice by qPCR, as detailed in Methods. * p<0.05 in a two-sided independent t-test.
Mentions: We next investigated whether PPAR β/δ antagonists are able to reverse established skin disease. For this experiment, we administered the agonist GW501516 orally in order to allow twice – daily topical application of the antagonist without possible interference with drug penetration. We thus induced skin disease by oral dosing of GW501516, using a modified dosing regimen to that previously described as detailed in Methods. Three weeks after initiation of treatment with antagonists, mice were sacrificed and skin samples analysed. As shown in figure 6a, both PPAR β/δ antagonists were able to partially reverse epidermal hyperplasia. The influx of both CD4+ and CD8+ T lymphocyte subsets was also reduced, as shown in figure 6b. (cell numbers were too low to allow quantification of IL17+ T cell subsets). Finally, we also quantified expression levels of genes previously shown to be induced by PPAR β/δ in the skin [21], HB-EGF, a direct target gene of PPAR β/δ [22], as well as two strongly induced indirect target genes, IL1b and LCE3e. As shown in figure 6c, the upregulation of both HB-EGF and LCE3e was partially reversed by treatment with both PPAR β/δ antagonists, although this reached statistical significance only for LCE3e. Reversal of IL1b expression was only observed using the ointment containing GSK0660. Taken together, these data show that transdermal application of PPAR β/δ antagonists is able to reverse established psoriasis-like disease in PPAR β/δ transgenic mice.

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Show MeSH
Related in: MedlinePlus