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[2, 6-dimethoxy-1, 4-benzoquinone alleviates septic shock in mice by inhibiting NLRP3 inflammasome activation]
Objective:
To investigate the mechanism of 2, 6-dimethoxy-1, 4-benzoquinone (DMQ), an active ingredients in fermented wheat germ extract, for inhibiting NLRP3 inflammasome activation and alleviating septic shock in mice.
Methods:
Cultured murine bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS) were treated with DMQ, followed by treatment with Nigericin, ATP, and MSU for activating the canonical NLRP3 inflammasome; the noncanonical NLRP3 inflammasome was activated by intracellular transfection of LPS, and AIM2 inflammasome was activated using Poly A: T.In human monocytic THP-1 cells, the effect of Nigericin on inflammasome activation products was examined using Western blotting and ELISA.Co-immunoprecipitation was performed to explore the mechanism of DMQ-induced blocking of NLRP3 inflammasome activation.In a male C57BL/6J mouse model of LPS-induced septic shock treated with 20 and 40 mg/kg DMQ, the levels of IL-1β and TNF-α in the serum and peritoneal lavage fluid were determined using ELISA, and the survival time of the mice within 36 h was observed.
Results:
Treatment with DMQ effectively inhibited LPS-induced activation of canonical NLRP3 inflammasome in mouse BMDM and human THP-1 cells and also inhibited non-canonical NLRP3 inflammasome activation in mouse BMDM, but produced no significant effect on AIM2 inflammasome activation.DMQ significantly blocked the binding between ASC and NLRP3.In the mouse models of septic shock, DMQ treatment significantly reduced the levels of IL-1β in the serum and peritoneal fluid and obviously prolonged survival time of the mice.
Conclusion:
DMQ can effectively block ASC-NLRP3 interaction to inhibit NLRP3 inflammasome activation and alleviate LPSinduced septic shock in mice.
Insights
2,6-dimethoxy-1,4-benzoquinone (DMQ) inhibits the NLRP3 inflammasome by blocking ASC-NLRP3 interaction. This mechanism alleviates septic shock in mice, reducing inflammatory cytokines and improving survival.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Context:
- The NLRP3 inflammasome is a key mediator of inflammatory diseases and septic shock.
- Fermented wheat germ extract contains active compounds with potential therapeutic properties.
- Understanding the molecular mechanisms of these compounds is crucial for drug development.
Purpose:
- To investigate the inhibitory mechanism of 2,6-dimethoxy-1,4-benzoquinone (DMQ) on NLRP3 inflammasome activation.
- To evaluate the efficacy of DMQ in alleviating lipopolysaccharide (LPS)-induced septic shock in a mouse model.
Summary:
- DMQ inhibited both canonical and non-canonical NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDM) and human THP-1 cells, but did not affect AIM2 inflammasome activation.
- DMQ was found to block the interaction between ASC and NLRP3, thereby inhibiting inflammasome assembly.
- In vivo studies demonstrated that DMQ treatment significantly reduced serum IL-1β levels and prolonged survival in LPS-induced septic shock mouse models.
Impact:
- This study elucidates a novel mechanism by which DMQ modulates inflammasome activity.
- DMQ shows therapeutic potential for treating inflammatory conditions like septic shock.
- The findings provide a basis for further research into DMQ and related compounds as anti-inflammatory agents.
