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Macrophages treated with particulate matter PM 2.5 induce selective neurotoxicity through glutaminase‐mediated glutamate generation
Author(s) -
Liu Fang,
Huang Yunlong,
Zhang Fang,
Chen Qiang,
Wu Beiqing,
Rui Wei,
Zheng Jialin C.,
Ding Wenjun
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13135
Subject(s) - neurotoxicity , glutaminase , microglia , glutamate receptor , extracellular , viability assay , nmda receptor , blood–brain barrier , microbiology and biotechnology , biology , chemistry , pharmacology , immunology , inflammation , biochemistry , central nervous system , in vitro , receptor , toxicity , endocrinology , organic chemistry
Exposure to atmospheric particulate matter PM 2.5 (aerodynamic diameter ≤ 2.5 μm) has been epidemiologically associated with respiratory illnesses. However, recent data have suggested that PM 2.5 is able to infiltrate into circulation and elicit a systemic inflammatory response. Potential adverse effects of air pollutants to the central nervous system ( CNS ) have raised concerns, but whether PM 2.5 causes neurotoxicity remains unclear. In this study, we have demonstrated that PM 2.5 impairs the tight junction of endothelial cells and increases permeability and monocyte transmigration across endothelial monolayer in vitro , indicating that PM 2.5 is able to disrupt blood–brain barrier integrity and gain access to the CNS . Exposure of primary neuronal cultures to PM 2.5 resulted in decrease in cell viability and loss of neuronal antigens. Furthermore, supernatants collected from PM 2.5 ‐treated macrophages and microglia were also neurotoxic. These macrophages and microglia significantly increased extracellular levels of glutamate following PM 2.5 exposure, which were negatively correlated with neuronal viability. Pre‐treatment with NMDA receptor antagonist MK 801 alleviated neuron loss, suggesting that PM 2.5 neurotoxicity is mediated by glutamate. To determine the potential source of excess glutamate production, we investigated glutaminase, the main enzyme for glutamate generation. Glutaminase was reduced in PM 2.5 ‐treated macrophages and increased in extracellular vesicles, suggesting that PM 2.5 induces glutaminase release through extracellular vesicles. In conclusion, these findings indicate PM 2.5 as a potential neurotoxic factor, crucial to understanding the effects of air pollution on the CNS .We propose the following cascade of events for PM 2.5 ‐induced neurotoxicity: PM 2.5 is inhalable and able to infiltrate into circulation. Circulating PM 2.5 impairs tight junction of endothelial cells, disrupts blood–brain barrier integrity, and gains access to the central nervous system. PM 2.5 induces neuronal injury directly or through macrophages and microglia by the elevated production of glutamate. The discovery of this cascade of events supports an adverse effect of air pollution on the central nervous system.