Wang Peng, Killeen Meaghan E, Sumpter Tina L, Ferris Laura K, Falo Louis D, Freeman Bruce A, Schopfer Francisco J, Mathers Alicia R
Departments of Dermatology, University of Pittsburgh School of Medicine. Pittsburgh, PA 15261, USA.
Departments of Dermatology, University of Pittsburgh School of Medicine. Pittsburgh, PA 15261, USA; Immunology, University of Pittsburgh School of Medicine. Pittsburgh, PA 15261, USA.
Redox Biol. 2021 Jul;43:101987. doi: 10.1016/j.redox.2021.101987. Epub 2021 Apr 24.
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 (NO-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 NO-FAs on psoriasiform dermatitis, we employed multiple murine models of psoriasis. Our studies demonstrate that oral treatment with nitro oleic acid (OA-NO) has both preventative and therapeutic effects on psoriasiform inflammation. In line with this finding, oral OA-NO downregulated the production of inflammatory cytokines in the skin. In vitro experiments demonstrate that OA-NO 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-NO 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.
银屑病是一种无法治愈的慢性炎症性皮肤病。尽管银屑病的起源及其潜在的病理生理学仍未完全了解，但炎症是疾病进展的核心介质。在这方面，亲电子硝基脂肪酸（NO-FAs）在几种炎症性疾病的体内小鼠模型中发挥强大的抗炎作用，如慢性肾病和心血管疾病。为了研究NO-FAs对银屑病样皮炎的治疗潜力，我们采用了多种银屑病小鼠模型。我们的研究表明，口服硝基油酸（OA-NO）对银屑病样炎症具有预防和治疗作用。与此发现一致，口服OA-NO可下调皮肤中炎性细胞因子的产生。体外实验表明，OA-NO通过抑制NF-κB磷酸化降低了人皮肤成纤维细胞中基础IL-6水平以及IL-17A诱导的IL-6表达。重要的是，OA-NO通过STAT3的硝基烷基化减少了STAT3磷酸化和核转位，从而抑制角质形成细胞增殖。总体而言，我们的结果证实了NF-κB和STAT3在银屑病样皮炎诱发中的关键作用，并突出了小分子硝基烯烃在治疗银屑病等皮肤炎性疾病方面的药理潜力。
