The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability.
Central nervous system (CNS) inflammation and autophagy dysfunction are known to be involved in the pathology of neurodegenerative diseases. Manganese (Mn), a neurotoxic metal, has the potential to induce microglia-mediated neuroinflammation as well as autophagy dysfunction. NLRP3 (NLR family, pyrin domain containing 3)- CASP1 (caspase 1) inflammasome-mediated neuroinflammation in microglia has specific relevance to neurological diseases. However, the mechanism driving these phenomena remains poorly understood. We demonstrate that Mn activates the NLRP3-CASP1 inflammasome pathway in the hippocampus of mice and BV2 cells by triggering autophagy-lysosomal dysfunction. The autophagy-lysosomal dysfunction is induced by lysosomal damage caused by excessive Mn accumulation, damaging the structure and normal function of these organelles. Additionally, we show that the release of lysosomal CTSB (cathepsin B) plays an important role in Mn-induced NLRP3-CASP1 inflammasome activation, and that the increased autophagosomes in the cytoplasm are not the main cause of NLRP3-CASP1 inflammasome activation. The accumulation of proinflammatory cytokines, such as IL1B (interleukin 1 β) and IL18 (interleukin 18), as well as the dysfunctional autophagy pathway may damage hippocampal neuronal cells, thus leading to hippocampal-dependent impairment in learning and memory, which is associated with the pathogenesis of Alzheimer disease (AD).
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Diya
D
Wang
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Jianbin
J
Zhang
b State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology , Department of Operative Dentistry & Endodontics , School of Stomatology, Fourth Military Medical University , Xi'an , Shaanxi , China.
Wenkai
W
Jiang
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Zipeng
Z
Cao
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Fang
F
Zhao
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Tongjian
T
Cai
c Department of Molecular Pharmacology , Albert Einstein College of Medicine , Bronx , NY , USA.
Michael
M
Aschner
a Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment , School of Public Health, Fourth Military Medical University , Xi'an , China.
Wenjing
W
Luo
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects*; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D007858:Learning / Q000502:physiology*; D008345:Manganese / Q000494:pharmacology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*
D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D008345:Manganese; D020170:Caspase 1
NLRP3 inflammasome; autophagy; manganese; microglia; neuroinflammation