Activation of NLRP3 in microglia exacerbates diesel exhaust particles-induced impairment in learning and memory in mice

Xiaobo Li; Yanshu Zhang; Bin Li; Hongbao Yang; Jian Cui; Xiaoyan Li; Xinwei Zhang; Hao Sun; Qingtao Meng; Shenshen Wu; Shuang Li; Jianbo Wang; Michael Aschner; Rui Chen

doi:10.1016/j.envint.2020.105487

Activation of NLRP3 in microglia exacerbates diesel exhaust particles-induced impairment in learning and memory in mice

Environ Int. 2020 Mar:136:105487. doi: 10.1016/j.envint.2020.105487. Epub 2020 Jan 27.

Authors

Xiaobo Li¹, Yanshu Zhang², Bin Li¹, Hongbao Yang³, Jian Cui¹, Xiaoyan Li¹, Xinwei Zhang¹, Hao Sun¹, Qingtao Meng¹, Shenshen Wu¹, Shuang Li², Jianbo Wang⁴, Michael Aschner⁵, Rui Chen⁶

Affiliations

¹ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
² Laboratory Animal Center, North China University of Science and Technology, Tangshan 063210, China.
³ Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
⁴ School of Public Health, North China University of Science and Technology, Tangshan 063210, China.
⁵ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: Michael.Aschner@einstein.yu.edu.
⁶ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: 101011816@seu.edu.cn.

PMID: 31999974
DOI: 10.1016/j.envint.2020.105487

Abstract

Background: The major components of traffic pollution particulate matter, diesel exhaust particles (DEPs), are airborne ultrafine particles (UFPs). DEPs can enter the central nervous system (CNS), where they may cause neurotoxicity.

Methods: We established murine models with intranasal DEPs instillation in male C57BL/6 and Nlrp3 knock-out (Nlrp3^-/-) mice to investigate the effects of DEPs exposure on murine neurobehaviors and related mechanisms. Morris water maze (MWM) tests were performed to evaluate the learning and memory behaviors of mice following DEPs instillation. Metabolomics were assessed using an gas chromatography system coupled to a mass spectrometer. Real-time PCR and immunohistochemistry assays were used to analyze the mRNA and protein expression levels of target genes. Murine microglia, BV2 cells were employed to assay the effects of DEPs exposure in vitro.

Results: Intranasal administration of DEPs in mice led to impairment in hippocampal-dependent learning and memory. Moreover, this phenotype was linked to increased number of Iba-1⁺ microglia and NLRP3 inflammasome, as well as suppression of mitochondrial gene expression in the hippocampus of mice exposed to DEPs. Nlrp3^-/- mice were resistant to DEPs-induced learning and memory impairment, concomitant with protection against the suppression of mitochondrial gene expression. Murine microglia cells (BV2) were exposed to DEPs in vitro and taurine was identified as one of the significantly suppressed metabolites in DEPs-treated microglia by metabolomics analysis. Supplementation with taurine efficiently rescued learning, memory and mitochondrial gene expression levels in the hippocampus of DEPs-exposed mice.

Conclusions: Mechanistically, our study revealed that microglia-mediated NLRP3 inflammasome activation plays a deleterious role in DEPs-induced neurotoxicity by inhibiting mitochondrial gene expression. These results shed novel light on the potential value of nutritional supplementation against DEPs-induced neurotoxicity in individuals exposed to severe airborne traffic-related air pollutions.

Keywords: Diesel exhaust particles (DEPs); Inflammasome; Microglia; NLRP3; Taurine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Learning
Male
Memory
Memory Disorders* / chemically induced
Memory Disorders* / genetics
Mice
Mice, Inbred C57BL
Microglia*
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Vehicle Emissions* / toxicity

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Vehicle Emissions

Grants and funding

R01 ES020852/ES/NIEHS NIH HHS/United States