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Published on: January 30, 2014
Pogostone Suppresses Microglial NLRP3 Inflammasome Activation-Promoted Remyelination Through RXRγ Regulation of
Menghan Qian1, Xingzong Sun1, Yue Jia2
1School of Medicine, Yunnan University, Kunming, China.
Abstract:
Multiple sclerosis (MS) is a chronic autoimmune disease involving central nervous system nerve demyelination accompanied by intense neuroinflammation. Pogostone (PO), a major component of Pogostemon cablin , has anti-inflammatory, immunosuppressive, and antioxidant properties. In this study, we characterized the therapeutic potential of PO in remyelination and elucidated the underlying mechanisms. In cuprizon (CPZ)-induced demyelinating mice, rotarod test, RNA sequence, molecular docking, immunofluorescence, and western blotting were used to analyze the targets and signaling pathways involved in PO treatment. Meanwhile, the changes of mitophagy and NLRP3 inflammasome were detected after further treatment with RXRγ antagonist UVI3003. In lipopolysaccharide (LPS)-induced BV2 microglia, after interference with RXRγ or blockade of mitophagy by 3-methyladenine (3-MA), the effects of PO on mtROS, mitochondrial membrane potential (MMP), NLRP3 inflammasome and mitophagy were measured by flow cytometry, immunofluorescence and western blotting. PO treatment effectively promoted remyelination in the CPZ model, and this effect was achieved by activating RXRγ. Meanwhile, PO suppressed microglial NLRP3 inflammasome activation through enhancement of PINK1/Parkin-mediated mitophagy, but this change was reversed by the RXRγ antagonist UVI3003. In LPS-induced BV2 microglia, interference with RXRγ reversed the inhibitory effect of PO on mtROS production, MMP decline, and NLRP3 activation. In addition, blockade of mitophagy by 3-MA reversed the inhibitory effects of PO on mtROS production and NLRP3 inflammasome activity. The present study demonstrated that PO suppresses microglial NLRP3 inflammasome activation-promoted remyelination via RXRγ regulation of mitophagy, which suggests PO as a promising drug candidate for the treatment of MS.
Insights
Pogostone (PO) promotes remyelination in multiple sclerosis (MS) by activating RXRγ and enhancing mitophagy, suppressing neuroinflammation. This suggests PO as a potential therapeutic agent for MS treatment.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease characterized by central nervous system demyelination and neuroinflammation.
- Pogostone (PO), derived from Pogostemon cablin, exhibits anti-inflammatory, immunosuppressive, and antioxidant properties.
- Understanding the therapeutic mechanisms of PO in remyelination is crucial for MS treatment.
Purpose of the Study:
- To investigate the therapeutic potential of Pogostone (PO) in promoting remyelination in a mouse model of multiple sclerosis (MS).
- To elucidate the underlying molecular mechanisms, focusing on the roles of RXRγ, mitophagy, and the NLRP3 inflammasome in PO's effects.
- To evaluate the impact of PO on microglial activation and inflammatory responses relevant to MS pathogenesis.
Main Methods:
- Cuprizone (CPZ)-induced demyelination mouse model and LPS-induced BV2 microglia model were utilized.
- Techniques included rotarod testing, RNA sequencing, molecular docking, immunofluorescence, western blotting, and flow cytometry.
- Interventions involved RXRγ antagonist (UVI3003) and mitophagy blockade (3-methyladenine, 3-MA) to dissect signaling pathways.
Main Results:
- PO treatment significantly promoted remyelination in the CPZ-induced MS model by activating RXRγ.
- PO suppressed microglial NLRP3 inflammasome activation via enhanced PINK1/Parkin-mediated mitophagy.
- RXRγ activation and mitophagy were essential for PO's inhibitory effects on mtROS production, MMP decline, and NLRP3 inflammasome activation.
Conclusions:
- Pogostone (PO) facilitates remyelination in MS by modulating microglial NLRP3 inflammasome activity through RXRγ-dependent regulation of mitophagy.
- These findings highlight the therapeutic potential of PO as a promising drug candidate for treating multiple sclerosis.
