In addition to the well-established effects of air pollution on the
cardiovascular and respiratory systems, emerging evidence has implicated it in
inducing negative effects on the central nervous system. Diesel exhaust
particulate matter (DEP), a major component of air pollution, is a complex
mixture of numerous toxicants. Limited studies have shown that DEP-induced
dopaminergic neuron dysfunction is mediated by microglia, the resident immune
cells of the brain. Here we show that mouse microglia similarly mediate primary
cerebellar granule neuron (CGN) death in vitro. While DEP (0,
25, 50, 100 µg/2 cm2) had no effect on CGN viability after 24
h of treatment, in the presence of primary cortical microglia neuronal cell
death increased by 2–3-fold after co-treatment with DEP, suggesting that
microglia are important contributors to DEP-induced CGN neurotoxicity. DEP (50
µg/2 cm2) treatment of primary microglia for 24 h resulted in
morphological changes indicative of microglia activation, suggesting that DEP
may induce the release of cytotoxic factors. Microglia-conditioned medium after
24 h treatment with DEP, was also toxic to CGNs. DEP caused a significant
increase in reactive oxygen species in microglia, however, antioxidants failed
to protect neurons from DEP/microglia-induced toxicity. DEP increased mRNA
levels of the pro-inflammatory cytokines IL-6 and IL1-β, and the release
of IL-6. The antibiotic minocycline (50 µM) and the peroxisome
proliferator-activated receptor-γ agonist pioglitazone (50 µM)
attenuated DEP-induced CGN death in the co-culture system. Microglia and CGNs
from male mice appeared to be somewhat more susceptible to DEP neurotoxicity
than cells from female mice possibly because of lower paraoxonase-2 expression.
Together, these results suggest that microglia-induced neuroinflammation may
play a critical role in modulating the effect of DEP on neuronal viability.