Silica-based nanoparticle uptake and cellular response by primary microglia.
BACKGROUND
Silica nanoparticles (SiNPs) are being formulated for cellular imaging and for nonviral gene delivery in the central nervous system (CNS), but it is unclear what potential effects SiNPs can elicit once they enter the CNS. As the resident macrophages of the CNS, microglia are the cells most likely to respond to SiNP entry into the brain. Upon activation, they are capable of undergoing morphological and functional changes.


OBJECTIVE
We examined the effects of SiNP exposure using primary rat microglia.


METHODS
We observed microglial uptake of SiNPs using transmission electron and fluorescence confocal microscopy. Microglial functions, including phagocytosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), expression of proinflammatory genes, and cytokine release, were measured after SiNP exposure at different concentrations.


RESULTS
Microglia are capable of avidly taking up SiNPs at all concentrations tested. These same concentrations did not elicit cytotoxicity or a change in phagocytic activity. SiNPs did increase the productions of both intracellular ROS and RNS. We also observed a significant decrease in tumor necrosis factor-alpha gene expression at all concentrations tested and a significant increase in COX-2 (cyclooxygenase-2) gene expression at the highest concentration of SiNPs. Analysis of cytokine release showed a detectable level of interleukin-1beta.


CONCLUSIONS
This is the first study demonstrating the in vitro effects of SiNPs in primary microglia. Our findings suggest that very low levels of SiNPs are capable of altering microglial function. Increased ROS and RNS production, changes in proinflammatory genes, and cytokine release may not only adversely affect microglial function but also affect surrounding neurons.
Choi
Judy
J
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
Zheng
Qingdong
Q
Katz
Howard E
HE
Guilarte
Tomás R
TR
D000818:Animals; D001693:Biological Transport, Active; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D053583:Interleukin-1beta / Q000096:biosynthesis; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage / Q000633:toxicity* / Q000648:ultrastructure; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D053583:Interleukin-1beta; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat