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NLRP3 activation in microglia contributes to learning and memory impairment induced by chronic lead exposure in mice
Jiawei Zhu1, Fan Zhou1, Qin Zhou1
1Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China.
Abstract:
Lead (Pb)-induced microglial activation and neuroinflammation has been considered as one of the main pathological events of Pb neurotoxicity. The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. However, the relationship between chronic Pb exposure and neurogenic NLRP3 inflammasome is unclear. Therefore, the aim of this study was to characterize the role of NLRP3 inflammasome activation during the chronic Pb exposure using in vitro and in vivo models. Our results showed that chronic Pb exposure induce learning and memory impairment in mice, mainly related to the activation of microglia and NLRP3 inflammasome. This phenomenon was reversed in mice by treating with the NLRP3 inhibitor MCC950 and using NLRP3-/- mice. In addition, Pb caused the activation of NLRP3 inflammasome, the production of mitochondrial ROS (mtROS), and mitochondrial Ca2+ overload in BV2 cells. Amelioration of mtROS abolished Pb-induced NLRP3 inflammasome activation. Moreover, after regulation of Ca2+ redistribution, mtROS and NLRP3 inflammasome activation was restored. In conclusion, NLRP3 inflammasome activation in microglia plays a vital role in Pb neurotoxicity, by a novel mechanism of enhancing mtROS production and Ca2+ redistribution.
Insights
Chronic lead exposure impairs learning and memory by activating microglia and the NLRP3 inflammasome. Inhibiting NLRP3 or blocking mitochondrial ROS and calcium overload can reverse these neurotoxic effects.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Lead (Pb) neurotoxicity involves microglial activation and neuroinflammation.
- The NLRP3 inflammasome pathway is a key mediator of neuroinflammation.
- The precise role of NLRP3 inflammasome activation in chronic lead exposure remains unclear.
Purpose of the Study:
- To investigate the role of NLRP3 inflammasome activation in chronic lead exposure.
- To elucidate the underlying mechanisms of lead-induced neuroinflammation.
- To assess potential therapeutic interventions targeting NLRP3.
Main Methods:
- In vivo studies using mouse models of chronic lead exposure.
- In vitro studies using BV2 microglial cells.
- Pharmacological inhibition of NLRP3 using MCC950.
- Genetic deletion of NLRP3 (NLRP3-/- mice).
- Assessment of mitochondrial reactive oxygen species (mtROS) and calcium (Ca2+) levels.
Main Results:
- Chronic lead exposure induced learning and memory deficits in mice.
- Lead exposure activated microglia and NLRP3 inflammasome, which was reversed by MCC950 treatment and in NLRP3-/- mice.
- Lead exposure in BV2 cells activated NLRP3 inflammasome, increased mtROS production, and caused mitochondrial Ca2+ overload.
- Reducing mtROS production or regulating Ca2+ redistribution ameliorated lead-induced NLRP3 inflammasome activation.
Conclusions:
- NLRP3 inflammasome activation in microglia is crucial for lead neurotoxicity.
- Lead exposure promotes NLRP3 activation via enhanced mtROS production and altered Ca2+ redistribution.
- Targeting NLRP3 inflammasome represents a potential therapeutic strategy for lead neurotoxicity.
