Cheng Hank, Davis David A, Hasheminassab Sina, Sioutas Constantinos, Morgan Todd E, Finch Caleb E
Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.
USC Dornsife College, University of Southern California, Los Angeles, CA, 90089, USA.
J Neuroinflammation. 2016 Jan 26;13:19. doi: 10.1186/s12974-016-0480-3.
The basis for air pollution-associated neurodegenerative changes in humans is being studied in rodent models. We and others find that the ultrafine particulate matter (PM) derived from vehicular exhaust can induce synaptic dysfunction and inflammatory responses in vivo and in vitro. In particular, a nano-sized subfraction of particulate matter (nPM, PM0.2) from a local urban traffic corridor can induce glial TNFα production in mixed glia (astrocytes and microglia) derived from neonatal rat cerebral cortex.
Here, we examine the role of TNFα in neurite dysfunctions induced by nPM in aqueous suspensions at 12 μg/ml. First, we show that the proximal brain gateway to nPM, the olfactory neuroepithelium (OE), rapidly responds to nPM ex vivo, with induction of TNFα, activation of macrophages, and dendritic shrinkage. Cell interactions were further analyzed with mixed glia and neurons from neonatal rat cerebral cortex.
Microglia contributed more than astrocytes to TNFα induction by nPM. We then showed that the threefold higher TNFα in conditioned media (nPM-CM) from mixed glia was responsible for the inhibition of neurite outgrowth by small interfering RNA (siRNA) TNFα knockdown and by TNFα immunoneutralization. Despite lack of TNFR1 induction by nPM in the OE, experimental blocking of TNFR1 by TNFα receptor blockers restored total neurite length.
These findings implicate microglia-derived TNFα as a mediator of nPM in air pollution-associated neurodegenerative changes which alter synaptic functions and neuronal growth.
目前正在啮齿动物模型中研究空气污染相关的人类神经退行性变化的基础。我们和其他人发现，源自汽车尾气的超细颗粒物（PM）可在体内和体外诱导突触功能障碍和炎症反应。特别是，来自当地城市交通走廊的纳米级颗粒物亚组分（nPM，PM0.2）可诱导新生大鼠大脑皮质混合神经胶质细胞（星形胶质细胞和小胶质细胞）产生胶质肿瘤坏死因子α（TNFα）。
在此，我们研究了TNFα在12μg/ml水悬浮液中nPM诱导的神经突功能障碍中的作用。首先，我们表明nPM进入大脑的近端通道，即嗅神经上皮（OE），在体外对nPM有快速反应，表现为TNFα的诱导、巨噬细胞的激活和树突收缩。我们进一步用新生大鼠大脑皮质的混合神经胶质细胞和神经元分析了细胞间相互作用。
在nPM诱导TNFα产生方面，小胶质细胞比星形胶质细胞起的作用更大。然后我们表明，混合神经胶质细胞条件培养基（nPM-CM）中高三倍的TNFα通过小干扰RNA（siRNA）敲低TNFα和TNFα免疫中和作用，导致神经突生长受到抑制。尽管nPM在OE中未诱导肿瘤坏死因子受体1（TNFR1），但用TNFα受体阻滞剂对TNFR1进行实验性阻断可恢复总神经突长度。
这些发现表明，小胶质细胞衍生出的TNFα是空气污染相关神经退行性变化中nPM的一种介质，这种变化会改变突触功能和神经元生长。
