Tempol Ameliorates Psoriatic Skin Inflammation: Evidence of TLR4/NF‐κB/Nrf2 Axis Modulation

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Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, immune dysregulation, oxidative stress, and impaired epidermal barrier function. In the present study, we investigated the protective effects of Tempol, a membrane-permeable nitroxide with antioxidant and anti-inflammatory properties, using several psoriasiform models. In HaCaT keratinocytes, stimulation with a cytokine mixture significantly induced inflammatory responses. Tempol (0.5 and 1 mM) showed no cytotoxic effects and markedly reduced the mRNA and protein levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6. Tempol was associated with reduced expression of TLR4, MyD88, TRAF6, and nuclear factor-kappa B (NF-κB), together with restoration of IκBα expression, findings consistent with modulation of the TLR4/NF-κB signaling pathway. In parallel, Tempol was associated with activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 antioxidant axis, as evidenced by increased expression of Nrf2, HO-1, and MnSOD, along with a reduction in the pro-oxidant enzymes NOX2 and NOX4. These effects were associated with decreased oxidative damage, including reduced lipid peroxidation and nitric oxide production. Furthermore, Tempol exerted cytoprotective effects by restoring the balance between pro- and antiapoptotic markers, as indicated by increased Bcl-2 levels, decreased Bax and p53 expression, and a reduced Bax/Bcl-2 ratio. The anti-inflammatory activity of Tempol was further confirmed in an imiquimod (IMQ)-stimulated HaCaT/THP-1 coculture model, where it significantly reduced the release of key immune mediators, including TLR4, IL-8, IL-17A, and IL-23, highlighting its ability to modulate immune-epithelial crosstalk. In a reconstructed human epidermis (RHE) model, Tempol preserved tissue viability under psoriasiform conditions and significantly reduced Staphylococcus aureus (S. aureus) adhesion. Importantly, Tempol restored epidermal barrier integrity, as demonstrated by increased levels of tight junction and differentiation markers, including ZO-1, Occludin, Claudin-1, and Filaggrin, even under infection-associated conditions. Taken as a whole, these findings support the potential of Tempol as a promising therapeutic strategy for psoriasis and related inflammatory skin disorders.

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