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 (≤ 2.5 μ m) 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)-κ 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 (). Exposure of the BV2 microglia to LP CAPs reduced intracellular levels of ATP (≥ 250 μ g/ml) and depolarized mitochondrial membranes (≥ 6 μ g/ml) within 15 min of exposure. HP and LP CAPs (≥ 25 μ g/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) α and interleukin (IL)-6 after 6 h of exposures. Microarray analysis of BV2 microglia exposed to either HP or LP CAPs (75 μ g/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.