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.
Highlights
One prominent clinical aspect of psoriasis is the clinical overlap with metabolic syndrome [1] and its association with increased body mass index [2], indicative of overlapping signalling pathways in psoriasis and other disorders of metabolism and chronic inflammation
The gene dysregulation profile induced by epidermal Peroxisome proliferator activated receptors (PPAR) b/d activation significantly overlaps with that characteristic of psoriasis, including faithful replication of well recognised functional clusters such as the entire Il1-module or the cholesterol biosynthesis program, suggesting that the subsets of genes dysregulated by PPAR b/d activation are regulated by PPAR b/d in psoriasis
These observations indicate that PPAR b/d signalling may contribute to the overlap between psoriasis and metabolic, as well as cardiovascular disease [10], since it is up-regulated in chronic inflammation and regulated by caloric intake [11,12]
Summary
One prominent clinical aspect of psoriasis is the clinical overlap with metabolic syndrome [1] and its association with increased body mass index [2], indicative of overlapping signalling pathways in psoriasis and other disorders of metabolism and chronic inflammation. The gene dysregulation profile induced by epidermal PPAR b/d activation significantly overlaps with that characteristic of psoriasis, including faithful replication of well recognised functional clusters such as the entire Il1-module or the cholesterol biosynthesis program, suggesting that the subsets of genes dysregulated by PPAR b/d activation are regulated by PPAR b/d in psoriasis. These observations indicate that PPAR b/d signalling may contribute to the overlap between psoriasis and metabolic, as well as cardiovascular disease [10], since it is up-regulated in chronic inflammation and regulated by caloric intake [11,12]. Several lines of evidence suggest that PPAR b/d activation contributes to psoriasis pathogenesis and that blocking its activation may reduce disease activity
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