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Sinomenine Regulates the TRIM32/IRF1/TRAF6 Axis to Inhibit Pyroptosis in Atopic Dermatitis.
Summary
Sinomenine, an alkaloid, reduces inflammation and pyroptosis in atopic dermatitis (AD) models. It works by degrading IRF1, downregulating TRAF6, and inhibiting the NLRP3 inflammasome, showing therapeutic potential for AD.
Area of Science:
- Dermatology
- Immunology
- Pharmacology
Background:
- Atopic dermatitis (AD) is a chronic inflammatory skin disease with immune dysregulation.
- Pyroptosis, a pro-inflammatory cell death, is implicated in AD pathogenesis.
- Sinomenine, a plant alkaloid, possesses anti-inflammatory properties but its role in AD-related pyroptosis is unclear.
Purpose of the Study:
- To investigate the effect of sinomenine on pyroptosis in an in vitro AD-like model.
- To elucidate the underlying molecular mechanism of sinomenine's action.
Main Methods:
- Established an in vitro AD-like model using HaCaT cells stimulated with IFN-γ and TNF-α.
- Assessed pyroptosis, inflammation, and cell damage using ELISA, MTT, LDH assays, flow cytometry, and Western blot.
- Explored mechanisms via ChIP-qPCR, luciferase assays, co-immunoprecipitation, and immunofluorescence.
Main Results:
- IFN-γ/TNF-α induced significant pyroptosis, characterized by elevated inflammatory cytokines (IL-18, IL-6, IL-8, IL-1β) and NLRP3 inflammasome activation (NLRP3, cleaved Caspase-1, GSDMD-N).
- Sinomenine pretreatment attenuated pyroptosis, reduced inflammatory markers, and improved cell viability.
- Sinomenine downregulated TRAF6 by inhibiting IRF1 transcription and enhancing TRIM32-mediated IRF1 degradation, thus disrupting the IRF1/TRAF6/NLRP3 axis.
Conclusions:
- Sinomenine effectively protects HaCaT cells from IFN-γ/TNF-α-induced pyroptosis.
- The mechanism involves promoting TRIM32-mediated IRF1 degradation, leading to TRAF6 downregulation and NLRP3 inflammasome inhibition.
- Sinomenine demonstrates significant therapeutic potential for treating inflammatory skin diseases like atopic dermatitis.
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