Macrophages treated with particulate matter <scp>PM</scp>_2.5 induce selective neurotoxicity through glutaminase‐mediated glutamate generation

<jats:title>Abstract</jats:title><jats:p>Exposure to atmospheric particulate matter <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> (aerodynamic diameter ≤ 2.5 μm) has been epidemiologically associated with respiratory illnesses. However, recent data have suggested that <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> is able to infiltrate into circulation and elicit a systemic inflammatory response. Potential adverse effects of air pollutants to the central nervous system (<jats:styled-content style="fixed-case">CNS</jats:styled-content>) have raised concerns, but whether <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> causes neurotoxicity remains unclear. In this study, we have demonstrated that <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> impairs the tight junction of endothelial cells and increases permeability and monocyte transmigration across endothelial monolayer <jats:italic>in vitro</jats:italic>, indicating that <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> is able to disrupt blood–brain barrier integrity and gain access to the <jats:styled-content style="fixed-case">CNS</jats:styled-content>. Exposure of primary neuronal cultures to <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> resulted in decrease in cell viability and loss of neuronal antigens. Furthermore, supernatants collected from <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub>‐treated macrophages and microglia were also neurotoxic. These macrophages and microglia significantly increased extracellular levels of glutamate following <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> exposure, which were negatively correlated with neuronal viability. Pre‐treatment with <jats:styled-content style="fixed-case">NMDA</jats:styled-content> receptor antagonist <jats:styled-content style="fixed-case">MK</jats:styled-content>801 alleviated neuron loss, suggesting that <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> 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 <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub>‐treated macrophages and increased in extracellular vesicles, suggesting that <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> induces glutaminase release through extracellular vesicles. In conclusion, these findings indicate <jats:styled-content style="fixed-case">PM</jats:styled-content><jats:sub>2.5</jats:sub> as a potential neurotoxic factor, crucial to understanding the effects of air pollution on the <jats:styled-content style="fixed-case">CNS</jats:styled-content>. <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13135-fig-0007-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p><jats:p>We propose the following cascade of events for PM<jats:sub>2.5</jats:sub>‐induced neurotoxicity: PM<jats:sub>2.5</jats:sub> is inhalable and able to infiltrate into circulation. Circulating PM<jats:sub>2.5</jats:sub> impairs tight junction of endothelial cells, disrupts blood–brain barrier integrity, and gains access to the central nervous system. PM<jats:sub>2.5</jats:sub> 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. </jats:p>