Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes

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.

Endocytotic Potential Governs Magnetic Particle Loading in Dividing Neural Cells: Studying Modes of Particle Inheritance

“…This finding parallels our previous observations in NSCs, highlighting the neurocompatibility of the particles used [8]. The safety profile of these MPs could be attributable to the slow degradation profile of the PLA matrix component (limiting the rate at which iron leaches from degrading particles; rapid leaching is a major correlate of MP toxicity [40,41]), and is also consistent with the observed stability of intracellular MPs in astrocytes [7]. We have used histological analyses to evaluate particle safety, however astrocytes participate in complex signaling pathways and secrete several biomolecules needed for homeostatic function [16,18,19].…”

Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model

“…30,31 However, our results are in contrast to other studies that show IONP-induced ROS production. [32][33][34][35] Possible explanations for the discrepancies include one or more of the following factors: different types and sizes of IONPs used; different surface properties (eg, surface coatings) of the IONPs that affect the degradation potential and thus the exposure to the naked iron oxide core and the liberation of iron ions that might induce ROS; 32 different cell types used; higher IONP concentration; different (mostly longer) incubation times after which ROS production was measured and/or different methods for assessing intracellular ROS.…”

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

“…61,62 Additionally, lysosome is vulnerable to ROS generated by NPs. 63 Accordingly, although the lysosome plays an integral part in the degradation stage of autophagy by fusing with the autophagosome to generate the autolysosome, SiNPsmediated lysosome impairment would cause a continued accumulation of autophagosomes, and ultimately disturbance of autophagy. [64][65][66] We did observe lysosome impairment after SiNPs exposure, which may be responsible for the autophagy disturbance ( Figure S1).…”