Electrophilic nitro-fatty acids suppress psoriasiform dermatitis: STAT3 inhibition as a contributory mechanism

Abstract

Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation is a central mediator of disease progression. In this regard, electrophilic nitro-fatty acids (NO2–FAs) exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease. To examine the therapeutic potential of NO2–FAs on psoriasiform dermatitis, we employed multiple murine models of psoriasis. Our studies demonstrate that oral treatment with nitro oleic acid (OA-NO2) has both preventative and therapeutic effects on psoriasiform inflammation. In line with this finding, oral OA-NO2 downregulated the production of inflammatory cytokines in the skin. In vitro experiments demonstrate that OA-NO2 decreased both basal IL-6 levels and IL-17A-induced expression of IL-6 in human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Importantly, OA-NO2 diminished STAT3 phosphorylation and nuclear translocation via nitroalkylation of STAT3, which inhibited keratinocyte proliferation. Overall, our results affirm the critical role of both NF-κB and STAT3 in the incitement of psoriasiform dermatitis and highlight the pharmacologic potential of small molecule nitroalkenes for the treatment of cutaneous inflammatory diseases, such as psoriasis.