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

Abstract

Abstract Psoriasis is a systemic, immune-mediated disorder, characterized by chronic inflammatory skin and joint manifestations. Electrophilic nitro-fatty acids (NO2-FAs) have been reported to exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease. To study the therapeutic potential of NO2-FAs on psoriasis, we employed both acute and chronic murine experimental models of psoriasis. Our studies demonstrate that oral treatments of nitro-oleic acid (OA-NO2), prior to imiquimod (IMQ) or rIL-23 treatments, significantly inhibited the induction of psoriasis-like inflammation and inflammatory cytokine production in the skin. Moreover, utilizing transgenic murine models of psoriasis, we determined that OA-NO2 had both a preventative and therapeutic effect on psoriasiform inflammation. Mechanistic in vitro experiments demonstrated that OA-NO2 decreased IL-17A-induced IL-6 expression in normal human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Importantly, OA-NO2 also impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus. Further mechanistic results indicated that OA-NO2 regulates STAT3 activation by post-translational modification of STAT3 via nitroalkylation. Overall, our results confirm the critical role of STAT3 in psoriasiform dermatitis and highlight the potential of NO2-FAs as therapeutic agents for the treatment of cutaneous inflammatory diseases, such as psoriasis.