NLRP3 activation in microglia contributes to learning and memory impairment induced by chronic lead exposure in mice

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.

Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17

“…A previous study has shown that Pb can induce microglial activation [ 8 ]. To determine whether Pb can promote microglial activation in AD pathology and whether neuronal injury is related to microglial activation, we determined the levels of the inflammatory cytokines TNF-α and IL-6 in the hippocampus tissue and serum of mice exposed to Pb as well as in the supernatant of BV-2 cells treated with Pb and Aβ 1-42 .…”

“…The damage to the CNS caused by Pb is primarily characterized by a decline in learning and memory abilities. This damage is directly linked to neuronal damage and neuroinflammation caused by Pb exposure [ 7 , 8 ] and may lead to Alzheimer's disease (AD), Parkinson's disease, and other neurodegenerative diseases [ 9 , 10 ].…”

SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis

“…A critical aspect that we examined was the effects of SELENOK on intracellular Ca 2+ flux. SELENOK deficiency, mediated via IP3R-associated ER Ca 2+ stores, leads to an overload of intracellular Ca 2+ , a state typically associated with cellular stress responses [ 57 , [72] , [73] , [74] ]. This poses an apparent contradiction to the diminished microglial immune response observed in SELENOK-deficient conditions, suggesting the existence of other pivotal mechanisms that influence microglial function.…”