Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes
Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes
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DOI：
10.3109/17435390.2015.1071445
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发表时间：
2016-03
期刊：
影响因子：
5
通讯作者：
C. Petters;K. Thiel;R. Dringen
中科院分区：
文献类型：
--
作者：
C. Petters;K. Thiel;R. Dringen
摘要氧化铁纳米颗粒（IONP）被用于各种生物医学和神经生物学应用。因此，非常有必要详细了解不同类型脑细胞的IONP积累和毒性潜力。文献数据表明，小胶质细胞比其他类型的脑细胞更容易受到IONP暴露的影响。为了研究IONP诱导的小胶质细胞毒性的机制，我们将荧光二巯基琥珀酸酯包被的IONP应用于小胶质细胞的原代培养。暴露于IONP 6 h引起小胶质细胞铁含量的强烈浓度依赖性增加，伴随着大量产生的活性氧（ROS）和细胞毒性。相比之下，几乎没有任何ROS染色和细胞活力的损失，观察培养的原代星形胶质细胞和神经元，虽然这些文化积累了类似的具体数额的IONP比小胶质细胞。与lysotracker的共定位研究表明，在小胶质细胞中孵育6小时后，而不是在星形胶质细胞和神经元中，大多数IONP荧光定位在溶酶体中。通过应用NH 4Cl或巴弗洛霉素A1中和溶酶体pH值以及铁螯合剂2，2 ′-联吡啶的存在，可以防止IONP处理的小胶质细胞培养物中ROS的形成和毒性。这些数据表明，在酸性pH值和铁催化的ROS产生的IONP诱导的毒性的小胶质细胞，并表明星形胶质细胞和神经元对急性IONP毒性的相对电阻从IONP的快速铁释放是一个缓慢的动员的结果，从IONP在溶酶体降解途径。
Abstract Iron oxide nanoparticles (IONPs) are used for various biomedical and neurobiological applications. Thus, detailed knowledge on the accumulation and toxic potential of IONPs for the different types of brain cells is highly warranted. Literature data suggest that microglial cells are more vulnerable towards IONP exposure than other types of brain cells. To investigate the mechanisms involved in IONP-induced microglial toxicity, we applied fluorescent dimercaptosuccinate-coated IONPs to primary cultures of microglial cells. Exposure to IONPs for 6 h caused a strong concentration-dependent increase in the microglial iron content which was accompanied by a substantial generation of reactive oxygen species (ROS) and by cell toxicity. In contrast, hardly any ROS staining and no loss in cell viability were observed for cultured primary astrocytes and neurons although these cultures accumulated similar specific amounts of IONPs than microglia. Co-localization studies with lysotracker revealed that after 6 h of incubation in microglial cells, but not in astrocytes and neurons, most IONP fluorescence was localized in lysosomes. ROS formation and toxicity in IONP-treated microglial cultures were prevented by neutralizing lysosomal pH by the application of NH4Cl or Bafilomycin A1 and by the presence of the iron chelator 2,2′-bipyridyl. These data demonstrate that rapid iron liberation from IONPs at acidic pH and iron-catalyzed ROS generation are involved in the IONP-induced toxicity of microglia and suggest that the relative resistance of astrocytes and neurons against acute IONP toxicity is a consequence of a slow mobilization of iron from IONPs in the lysosomal degradation pathway.