Electrophilic nitro-fatty acids suppress psoriasiform dermatitis through the inhibition of STAT3 and NF-κB

Abstract

Abstract Psoriasis is a systemic, immune-mediated disorder, characterized by chronic inflammatory skin and joint manifestations. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of endogenous electrophilic nitro-fatty acids that exert potent anti-inflammatory effects. To study the therapeutic potential of nitro-fatty acids on psoriasis, we employed various experimental models of psoriasis including direct induction and genetically engineered murine models. Our studies demonstrated that oral treatments of nitro-oleic acid (OA-NO2) prior to imiquimod (IMQ) or IL-23 applications, significantly inhibited the induction of psoriasis-like skin inflammation. Consistently, oral OA-NO2 downregulated the production of inflammatory cytokines (IL-1β, IL-6 and IL-17a) in the skin. Moreover, utilizing the chronic K14-VEGF and K5-IL-17C murine models, we determined that oral OA-NO2 had both a preventative and therapeutic effect on psoriasiform inflammation. Further in vitro experiments demonstrated that OA-NO2 impaired STAT3 phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. Importantly, OA-NO2 decreased the basal expression and IL-17A-induced expression of IL-6 in normal human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Overall, our results confirm the critical role of both STAT3 and NF-κB, in psoriasiform dermatitis, and highlight the potential of nitrofatty acids as therapeutic agents for the treatment of this cutaneous inflammatory disease.