Date Published: October 15, 2018
Publisher: Public Library of Science
Author(s): Julalak Chorachoo, Sylviane Lambert, Teal Furnholm, Liza Roberts, Laura Reingold, Sauvarat Auepemkiate, Supayang P. Voravuthikunchai, Andrew Johnston, Miroslav Blumenberg.
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.
Psoriasis is a common and chronic autoimmune inflammatory skin disorder that has a prevalence of 2–3% in the world’s population . The disease is clinically characterized by red, scaly, and well-demarcated skin lesions that are a consequence of epidermal hyperplasia, altered keratinocyte differentiation, and a dense dermal inflammatory infiltrate. Although the disease pathogenesis is still not fully understood, many lines of evidence suggest that psoriasis epidermal inflammation is mainly driven by activated T cells . Cytokines play a central role in the psoriasis disease process , particularly IL-17A and TNF-α, as highlighted by the efficacy of recently-developed biologic drugs targeting these molecules in psoriasis [4, 5]. Despite their efficacy, biologics have a number of significant caveats, including expense, need for injection/infusion, adverse reactions, and loss of efficacy over time  thus there is an ongoing need for discovery of new biological targets and novel therapeutics.
Psoriasis lesions contain elevated levels of TNF-α  and IL-17A, cytokines recognized as important mediators of cutaneous inflammation [18, 23, 24]. Biologics targeting TNF-α [4, 5] and IL-17A [25, 26] have been developed and found to be very effective for managing psoriasis. Despite their efficacy, these biologics have a number of drawbacks and side effects. Because of their high molecular weight, biologics have to be administered by injection or infusion and are expensive to produce. Biologics can lose efficacy over time and may trigger a number of side-effects including speckled hyperpigmentation , increased risk of infection [6, 28], as well as the development of secondary autoimmune diseases including cutaneous vasculitis, hematological diseases, and other autoimmune diseases [29, 30]. Therefore, there remains a need for the development of effective and inexpensive oral or topical psoriasis treatments.