Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes.
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.
a Center for Biomedical Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen , Bremen , Germany .|b Center for Environmental Research and Sustainable Technology , Bremen , Germany , and.
Charlotte
C
Petters
c Fraunhofer Institute for Manufacturing Technology and Advanced Materials , Bremen , Germany.
Karsten
K
Thiel
a Center for Biomedical Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen , Bremen , Germany .|b Center for Environmental Research and Sustainable Technology , Bremen , Germany , and.
Ralf
R
Dringen
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D058185:Magnetite Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D004113:Succimer / Q000737:chemistry
D058185:Magnetite Nanoparticles; D017382:Reactive Oxygen Species; D015082:2,2'-Dipyridyl; D004113:Succimer
Lysosomes; oxidative stress; protection; reactive oxygen species; toxicity