Resveratrol ameliorates Imiquimod-induced psoriasis-like skin inflammation in mice. Mus musculus

The polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to downregulate NF-κB; a major contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the observed effects. The study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, actual skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting. Imiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways (e.g.IL-17A, IL-17F,IL-23p19 ). Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis. In conclusion, resveratrol ameliorates psoriasis, and changes in expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner suggests it might have a role in the treatment of psoriasis and should be explored further in a human setting. Overall design: Three control mice, two mice with Imiquimod-induced psoriasis and two mice with Imiquimod-induced psoriasis treated with Resveratrol were used. The mice were distributed into 3 groups; a control group, an IMQ group and an IMQ-RSV (8, 10 and 10 mice per group). The mice in groups IMQ and IMQ-RSV received a daily dose of 62.5 mg of 5% IMQ cream (Aldara; MEDA AS) applied on their backs and right ear folds. The mice in the control group received a similar daily dose of vehicle cream (Vaseline Lanette cream; Fagron). The feed was pulverized (standard chow with protein, carbohydrate and fat accounting for 20%/70%/10% of caloric intake, respectively). Trans-RSV was added to the pulverized feed given to the IMQ-RSV group in an amount of 400 mg/kg animal/day based on average food intake. All animals were assessed for the severity of the psoriasis-like skin condition on days 0, 2, 4 and 7, using 2 elements of the Psoriasis Area Severity Index (PASI), to assign a score of 0-4 (0, none; 1, mild; 2, moderate; 3, severe; 4, very severe) for each of the parameters erythema and scaling. Omitting evaluation of induration by PASI, we used thickness of a skinfold on the back (day 7) and thickness of the right ear fold (day 0 and 7) measured by using a calliper (accuracy: 0,02mm, Mitsutomo, Japan). On day 7, the animals were euthanized and the shaved area of skin on their backs was immediately excised. A 4 mm punch biopsy of lesional skin was fixed in formalin and paraffin embedded for histological analysis. The remaining lesional skin was snap frozen in liquid nitrogen and stored at -80 C .