Inducible Nitric Oxide Deficiency Attenuates Necroptosis in Psoriasis-Like Dermatitis in Mice by Reducing Oxidative Stress.

Psoriasis is a chronic inflammatory disease characterized by abnormal inflammatory responses and epidermal hyperplasia. In the inflammatory cascade of psoriasis, necroptosis mediates inflammation-related keratinocyte (KC) death, which further amplifies both cell death and inflammation. In this study, we demonstrated that inducible nitric oxide synthase deficiency attenuated the necroptosis process by promoting the clearance of ROS, consequently mitigating imiquimod-induced inflammatory infiltration and expression levels of inflammatory mediators. After hydrogen peroxide stimulation in vitro, absence of inducible nitric oxide synthase significantly inhibited the activation of necroptotic pathway in KCs. In particular, topical application of nitric oxide not only inhibited the proliferation of KCs in psoriatic lesions but significantly reduced the ROS levels and necroptosis in KCs, which ultimately alleviated the progression of psoriasis-like dermatitis. Collectively, these results suggest that nitric oxide can influence the pathogenesis of psoriasis-like dermatitis by modulating the necroptotic pathway in KCs. This study emphasizes the pivotal role of necroptosis in the pathogenesis of psoriasis, while providing insights for the development of inducible nitric oxide synthase/nitric oxide-based therapeutic strategies for psoriasis.