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Targeting Nrf2 with 3 H-1,2-dithiole-3-thione to moderate OXPHOS-driven oxidative stress attenuates IL-17A-induced
Chuan-Teng Liu1, Jui-Hung Jimmy Yen2, Dennis A Brown3
1Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
Abstract:
Psoriasis, a chronic autoimmune disease characterized by the hyperproliferation of keratinocytes in the epidermis and parakeratosis, significantly impacts quality of life. Interleukin (IL)- 17A dominates the pathogenesis of psoriasis and facilitates reactive oxygen species (ROS) accumulation, which exacerbates local psoriatic lesions. Biologic treatment provides remarkable clinical efficacy, but its high cost and unignorable side effects limit its applications. 3 H-1,2-Dithiole-3-thione (D3T) possesses compelling antioxidative capacities against several diseases through the nuclear factor erythroid 2-related factor 2 (Nrf2) cascade. Hence, we aimed to evaluate the effect and mechanism of D3T in psoriasis. We found that D3T attenuates skin thickening and scaling by inhibiting IL-17A-secreting γδT cells in imiquimod (IMQ)-induced psoriatic mice. Interleukin-17A markedly enhanced IL-6 and IL-8 expression, lipid peroxidation, the contents of nitric oxide and hydrogen peroxide, oxidative phosphorylation and the MAPK/NF-κB pathways in keratinocytes. IL-17A also inhibited the Nrf2-NQO1-HO-1 axis and the activities of superoxide dismutase and glutathione peroxidase. D3T significantly reversed these parameters in IL-17A-treated keratinocytes. ML-385, a Nrf2 neutralizer, failed to improve D3T-induced anti-inflammatory and antioxidative effects in IL-17A-treated keratinocytes. We conclude that targeting Nrf2 with D3T to diminish oxidative and inflammatory damage in keratinocytes may attenuate psoriasis.
Insights
3H-1,2-Dithiole-3-thione (D3T) reduces psoriasis symptoms by inhibiting Interleukin-17A (IL-17A) and decreasing oxidative stress. D3T targets the Nrf2 pathway, offering a potential new treatment for this chronic autoimmune skin condition.
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.
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