Related Experiment Video
Updated: Sep 27, 2026
Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome
Xinrou Lin1, Hongxuan Wang2, Lubin Zou1
1Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China.
Background:
Chronic alcohol exposure induces cognitive impairment and NLRP3 inflammasome activation in the mPFC (medial prefrontal cortex). Mitophagy plays a crucial role in neuroinflammation, and dysregulated mitophagy is associated with behavioral deficits. However, the potential relationships among mitophagy, inflammation, and cognitive impairment in the context of alcohol exposure have not yet been studied. NRF2 promotes the process of mitophagy, while alcohol inhibits NRF2 expression. Whether NRF2 activation can ameliorate defective mitophagy and neuroinflammation in the presence of alcohol remains unknown.
Methods:
BV2 cells and primary microglia were treated with alcohol. C57BL/6J mice were repeatedly administered alcohol intragastrically. BNIP3-siRNA, PINK1-siRNA, CCCP and bafilomycin A1 were used to regulate mitophagy in BV2 cells. RTA-408 acted as an NRF2 activator. Mitochondrial dysfunction, mitophagy and NLRP3 inflammasome activation were assayed. Behavioral tests were used to assess cognition.
Results:
Chronic alcohol exposure impaired the initiation of both receptor-mediated mitophagy and PINK1-mediated mitophagy in the mPFC and in vitro microglial cells. Silencing BNIP3 or PINK1 induced mitochondrial dysfunction and aggravated alcohol-induced NLRP3 inflammasome activation in BV2 cells. In addition, alcohol exposure inhibited the NRF2 expression both in vivo and in vitro. NRF2 activation by RTA-408 ameliorated NLRP3 inflammasome activation and mitophagy downregulation in microglia, ultimately improving cognitive impairment in the presence of alcohol.
Conclusion:
Chronic alcohol exposure-induced impaired mitophagy initiation contributed to NLRP3 inflammasome activation and cognitive deficits, which could be alleviated by NRF2 activation via RTA-408.
Insights
Chronic alcohol use impairs mitophagy, increasing neuroinflammation and cognitive deficits. Activating NRF2 (Nuclear factor erythroid 2-related factor 2) with RTA-408 can restore mitophagy, reduce inflammation, and improve alcohol-induced cognitive impairment.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Chronic alcohol exposure causes cognitive impairment and NLRP3 inflammasome activation in the medial prefrontal cortex (mPFC).
- Mitophagy is vital for neuroinflammation; its dysregulation is linked to behavioral deficits.
- The interplay between mitophagy, inflammation, and cognitive decline in alcohol use is understudied, as is NRF2's role in mitigating these effects.
Purpose of the Study:
- To investigate the relationship between alcohol-induced mitophagy defects, neuroinflammation, and cognitive impairment.
- To determine if NRF2 activation can ameliorate alcohol-induced mitophagy dysfunction and neuroinflammation.
Main Methods:
- Assessed mitophagy, mitochondrial dysfunction, and NLRP3 inflammasome activation in alcohol-treated BV2 cells and microglia.
- Utilized C57BL/6J mice subjected to chronic alcohol administration.
- Employed BNIP3-siRNA, PINK1-siRNA, CCCP, bafilomycin A1 to modulate mitophagy, and RTA-408 as an NRF2 activator.
Main Results:
- Alcohol impaired mitophagy initiation in the mPFC and microglia, exacerbating NLRP3 inflammasome activation when mitophagy genes were silenced.
- Alcohol exposure reduced NRF2 expression both in vivo and in vitro.
- NRF2 activation with RTA-408 improved mitophagy, reduced NLRP3 inflammasome activation, and ameliorated cognitive deficits in alcohol-exposed subjects.
Conclusions:
- Impaired mitophagy initiation is a key factor in alcohol-induced neuroinflammation and cognitive deficits.
- NRF2 activation presents a potential therapeutic strategy to counteract alcohol's detrimental effects on mitophagy and cognition.
More Related Videos
09:02Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing
Published on: June 9, 2017
09:29Investigating Drivers of Antireward in Addiction Behavior with Anatomically Specific Single-Cell Gene Expression Methods
Published on: August 4, 2022
