The Cellular and Genomic Response of an Immortalized Microglia Cell Line (BV2) to Concentrated Ambient Particulate Matter

Abstract

Ambient particulate matter (PM) damages pulmonary tissue through oxidative stress (OS) pathways. Several reports indicate that the brain is another affected target of PM exposure. Since microglia (brain macrophages) are critical to OS-mediated neurodegeneration, the cellular and genomic response of immortalized mouse microglia (BV2) was examined in response to fine (<or= 2.5 microm) concentrated ambient particles (CAPs) collected from Tuxedo, NY. Samples of CAPs were labeled as high potency (HP) or low potency (LP) depending on their stimulation of nuclear factor (NF)-kappa B activity in human bronchial epithelial cells. Compositional analysis of these samples, performed during their original collection, indicated a strong correlation between HP CAPs and and the presence of nickel and vanadium (Maciejczyk & Chen, 2005). Exposure of the BV2 microglia to LP CAPs reduced intracellular levels of ATP (>or= 250 microg/ml) and depolarized mitochondrial membranes (>or= 6 microg/ml) within 15 min of exposure. HP and LP CAPs (>or= 25 microg/ml) differentially affected the endogenous scavengers, glutathione and nonprotein sulfhydryl in BV2 microglia after 1.5 h of exposure. Both HP and LP CAPs stimulated the release of proinflammatory cytokines tumor necrosis factor (TNF) alpha and interleukin (IL)-6 after 6 h of exposures. Microarray analysis of BV2 microglia exposed to either HP or LP CAPs (75 microg/ml, 4 h) identified 3200 (HP CAPs) and 160 (LP CAPs) differentially expressed (up- and downregulated) genes relative to media controls. Of the 3200 genes significantly affected by HP CAPs, the most prominent upregulated gene probes related to inflammatory pathways associated with Toll-like receptor signaling, MAPK signaling, T- and B-cell receptor signaling, apoptosis, and various proinflammatory cytokines and their receptors. LP CAPs significantly affected 160 genes that related to pathways associated with cellular maintenance and division, cell cycling and nuclear events. These data suggest that HP CAPs, which contained higher levels of nickel and vanadium than LP CAPs, appear to be more inflammatory and selectively upregulated the expression of inflammatory and innate immunity pathways in BV2 microglia.

Air pollution: mechanisms of neuroinflammation and CNS disease

“…Interestingly, microglia exposed in vitro to concentrated ambient air pollution upregulate mRNA of pro-inflammatory cytokines, such as IL-1β and TNFα 91, suggesting that some forms of PM may be able to cause cytokine production. Further, there is evidence that metals associated with air pollution activate microglia, as microglia are activated in vitro by manganese94, a component of industrial-derived air pollution.…”

Migraine Triggers and Oxidative Stress: A Narrative Review and Synthesis

“…Particulates can be transported along the axons, bypassing the blood‐brain barrier, and cross the synaptic cleft into the brain parenchyma . Based on in vitro evidence, the pollutants may activate microglial via toll‐like receptor signaling, inducing an inflammatory response and oxidative stress . Thus, the neurotoxicity of inhaled particulate matter (collected from a public park in Tuxedo, NY, and concentrated) is exacerbated in apolipoprotein E null rats, which are systemically prone to oxidative stress …”

Microglial priming through the lung—brain axis: the role of air pollution‐induced circulating factors

“…Consistent with human reports (13), animal studies have revealed that exposure to diverse forms of outdoor air pollution by inhalation, such as urban particulate matter (34, 35), O 3 (36), diesel exhaust (37–39), and manganese (40, 41), results in elevated cytokines and oxidative stress in the brain. More specifically, several inhaled air pollutants are shown to activate microglia with direct effects in vitro (38, 42, 43), in animal models (38, 44), and in human (13) studies.…”