Targeting Nrf2 with 3 H-1,2-dithiole-3-thione to moderate OXPHOS-driven oxidative stress attenuates IL-17A-induced...

Area of Science:

• Dermatology
• Immunology
• Oxidative Stress Research

Background:

• Psoriasis is a chronic autoimmune disease impacting quality of life, driven by keratinocyte hyperproliferation and Interleukin-17A (IL-17A).
• Current biologic treatments for psoriasis are effective but costly and have side effects.
• 3H-1,2-Dithiole-3-thione (D3T) exhibits antioxidative properties via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Purpose of the Study:

• To investigate the therapeutic effect and underlying mechanism of D3T in a mouse model of psoriasis.
• To determine if D3T can mitigate IL-17A-driven inflammation and oxidative damage in keratinocytes.

Main Methods:

• Utilized an imiquimod (IMQ)-induced mouse model of psoriasis.
• Assessed the impact of D3T on IL-17A-secreting γδT cells, keratinocyte signaling pathways, and oxidative stress markers.
• Investigated the role of the Nrf2 pathway using a Nrf2 neutralizer (ML-385).

Main Results:

• D3T treatment attenuated skin thickening and scaling in IMQ-induced psoriatic mice.
• D3T inhibited IL-17A-induced expression of IL-6, IL-8, nitric oxide, and hydrogen peroxide in keratinocytes.
• D3T reversed IL-17A-mediated inhibition of the Nrf2-NQO1-HO-1 axis and antioxidant enzyme activities, an effect not improved by Nrf2 neutralization.

Conclusions:

• D3T demonstrates anti-inflammatory and antioxidative effects in psoriasis by targeting IL-17A-producing cells and keratinocytes.
• The therapeutic benefits of D3T in this model are linked to modulating oxidative and inflammatory damage via the Nrf2 pathway.
• D3T represents a potential therapeutic agent for psoriasis, warranting further investigation into its Nrf2-dependent mechanisms.