Abstract
Psoriasis is a common skin disease pathogenically driven by TNF and IL-17A-induced epidermal hyperproliferation and inflammatory responses. The ongoing need for new therapeutic agents for psoriasis has highlighted medicinal plants as sources of phytochemicals useful for treating psoriatic disease. Rhodomyrtone, a bioactive phytochemical from Rhodomyrtus tomentosa, has well-established anti-proliferative activities. This study assessed the potential of rhodomyrtone for curtailing TNF/IL-17A-driven inflammation. Stimulating human skin organ cultures with TNF+IL-17A to model the skin inflammation in psoriasis, we found that rhodomyrtone significantly decreased inflammatory gene expression and the expression and secretion of inflammatory proteins, assessed by qRT-PCR, immunohistochemistry and ELISA assays respectively. RNA-seq analysis of monolayer primary keratinocytes treated with IL-17A/TNF showed that rhodomyrtone inhibited 724/1587 transcripts >2-fold altered by IL-17A/TNF (p<0.01), a number of which were confirmed at the mRNA and protein level. Suggesting that rhodomyrtone acts by modulating MAP kinase and NF-κB signaling pathways, rhodomyrtone inhibited TNF-induced ERK, JNK, p38, and NF-κBp65 phosphorylation. Finally, assessing the in vivo anti-inflammatory potential of rhodomyrtone, we examined its effects on imiquimod-induced skin inflammation in mice, finding rhodomyrtone reversed imiquimod-induced skin hyperplasia and epidermal thickening (p< 0.001). Taken together, these results suggest that rhodomyrtone may be useful in preventing or slowing the progression of inflammatory skin disease.
Highlights
Psoriasis is a common and chronic autoimmune inflammatory skin disorder that has a prevalence of 2–3% in the world’s population [1]
Cytokines play a central role in the psoriasis disease process [3], IL-17A and TNF-α, as highlighted by the efficacy of recently-developed biologic drugs targeting these molecules in psoriasis [4, 5]
We developed an ex vivo organotypic skin culture model using full-thickness normal human skin stimulated with IL-17A and TNF-α to mimic disease-related molecular changes in psoriasis skin
Summary
Psoriasis is a common and chronic autoimmune inflammatory skin disorder that has a prevalence of 2–3% in the world’s population [1]. We have previously shown that at high concentrations (>2 μg/ml), rhodomyrtone can cause growth arrest and apoptosis of the HaCaT keratinocyte cell line, and inhibit an in vitro wound-healing assay. These observations lead us to examine the potential of rhodomyrtone as a therapeutic for treating the skin disease psoriasis, which involves both activation of the immune system and cytokine-driven keratinocyte hyperproliferation [2]. Our findings suggest that rhodomyrtone is a candidate for further investigation as a new therapeutic for psoriasis treatment
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