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 pro-inflammatory 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-1 beta. 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 pro-inflammatory genes, and cytokine release may not only adversely affect microglial function but also affect surrounding neurons.