Photo-induced nitric oxide modulation in human skin: Impacts of geographic location and seasonality on health and disease.

Depending on geographic location and seasonality, human epidermal tissue is exposed to varying levels of solar radiation. Following light absorption by endogenous photosensitizers, solar photons generate reactive oxidants, inducing oxidative stress that is counteracted by nitric oxide, which inhibits lipid peroxidation and activates antioxidant signaling pathways. Nitric oxide is also quickly transformed in several more stable compounds, which can release nitric oxide at specific conditions, here called nitric oxide reserves. During sun exposure, photolysis of nitric oxide reserves releases bioactive nitric oxide, while inducible nitric oxide synthase is expressed later, synthesizing nitric oxide and replenishing nitric oxide stores. This dynamic process establishes a photoinduced steady state of nitric oxide release and storage. The balance between nitric oxide and reactive oxidants levels is regulated by solar radiation and fluctuates with seasonal and latitudinal variations. Sunlight exposure promotes bioactive nitric oxide production, helping to sustain a healthy nitric oxide/reactive oxidants equilibrium. However, this mechanism is disrupted in chronic inflammatory skin conditions. In this context, elevated expression of inducible nitric oxide synthase is commonly observed in patients with psoriasis, atopic dermatitis and vitiligo. These patients display nitric oxide dysregulation alongside impaired redox regulators, including Nrf2 and NADPH oxidase. Inducible nitric oxide synthase dysregulation, combined with upregulated NADPH oxidase, promotes peroxynitrite formation, further disrupting the nitric oxide-reactive oxidants balance. Pathological inducible nitric oxide synthase activation also leads to nitrite accumulation, impairing redox networks and cellular antioxidant systems. During winter months, reduced solar radiation decreases photolysis-derived nitric oxide and downregulates Nrf2, while inducible nitric oxide synthase and NADPH oxidase remain elevated, exacerbating these conditions. Similar effects occur at high latitudes. Photonic therapies aimed at restoring nitric oxide equilibrium have shown promise in treating such skin disorders.