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

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.