Macrophages treated with particulate matter PM2.5 induce selective neurotoxicity through glutaminase-mediated glutamate generation.

Exposure to atmospheric particulate matter PM_2.5 (aerodynamic diameter < 2.5 lm) 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 thatPM_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 MK801 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 indicatePM_2.5 as a potential neurotoxic factor, crucial to understanding the effects of air pollution on the CNS. [ABSTRACT FROM AUTHOR]