Urban airborne PM2.5-activated microglia mediate neurotoxicity through glutaminase-containing extracellular vesicles in olfactory bulb
2020
Chen, Xiaoyu | Guo, Jing | Huang, Yunlong | Liu, Shan | Huang, Ying | Zhang, Zezhong | Zhang, Fang | Lu, Zhongbing | Li, Fang | Zheng, Jialin C. | Ding, Wenjun
Emerging evidence has showed that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM₂.₅) is associated with neurodegeneration. Our previous studies in vitro found that PM₂.₅ exposure causes primary neurons damage through activating microglia. However, the molecular mechanism of microglia-mediated neurotoxicity remains to elucidate. In this study, five groups (N = 13 or 10) of six-week-old male C57BL/6 mice were daily exposed to PM₂.₅ (0.1 or 1 mg/kg/day body weight), Chelex-treated PM₂.₅ (1 mg/kg/day body weight), PM₂.₅ (1 mg/kg/day body weight) plus CB-839 (glutaminase inhibitor), or deionized water by intranasal instillation for 28 days, respectively. Compared with the control groups, We found that PM₂.₅ triggered reactive oxygen species (ROS) generation and microglia activation evidenced by significant increase of ionized calcium binding adaptor molecule-1 (IBa-1) staining in the mouse olfactory bulbs (OB). Data from transmission electron microscope (TEM) images and Western blot analysis showed that PM₂.₅ significantly increased extracellular vesicles (EVs) release from OB or murine microglial line BV2 cells, and glutaminase C (GAC) expression and glutamate generation in isolated OB and BV2 cells. However, treatment with N-acetylcysteine (NAC) or CB-839 significantly diminished the number of EVs and the expression of GAC and abolished PM₂.₅-induced neurotoxicity. These findings provide new insights that PM₂.₅ induces oxidative stress and microglia activation through its metal contents and glutaminase-containing EVs in OBs, which may serve as a potential pathway/mechanism of excessive glutamate generation in PM₂.₅-induced neurotoxicity.
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