Saturday, 15 February 2014
Crystal Ballroom A (Hyatt Regency Chicago)
Air pollution has been increasingly linked to central nervous system (CNS) disease, but the mechanisms driving this response and the type of exposures responsible are largely unknown. Microglia, the resident innate immune cell in the brain, and peripheral inflammation have been implicated in the progressive nature of neurodegenerative disease, but their role in air pollution-induced neuropathology is poorly understood. Diesel exhaust (DE) is a major component of near-road and urban pollution and has received significant attention regarding its human health effects in both ambient and occupational exposure conditions. To discern the early CNS response to diesel exhaust (DE), adult male rats were exposed to DE (2.0, 0.5, and 0 mg PM/m3) for one month by inhalation. DE-exposure elevated markers of neuroinflammation (nitrotyrosine, IL-6, TNFα, and MIP-1α) in the midbrain, cortex, and olfactory bulbs, in addition to activation of microglia, as determined by morphology. The highest levels of neuroinflammation occurred in the midbrain, which also contained the highest level of the IBA-1 microglial marker. Neurotoxicity and early markers of neurodegenerative disease were unaffected. One month exposure to biodiesel exhaust revealed only changes in microglia morphology without any elevation of pro-inflammatory factors, demonstrating that neuroinflammation may be exposure specific. In an effort to reveal how DE might be causing neuroinflammation, rats were administered an IT bolus of DE particles (DEP, 20 mg/kg) where DEP exposure elevated serum and brain TNFα, suggesting a role for the particles in initiating peripheral inflammation capable of transferring to the brain. Importantly, primary microglia cultures treated with DEP (50μg/ml) fail to produce TNFα, indicating that brain TNFα production may not be due to the direct interaction of microglia with the particles. To begin to explore the role of long-term exposure on CNS health, we tested the effect of subchronic (6 month) DE (992, 311, 100, 35 and 0 μg PM/m³) inhalation in rats and found elevated levels of the neurotoxic cytokine TNFα at lower exposures (DE, 100 μg PM/m³) and early protein markers of neurodegenerative diseases (Aβ42, α synuclein and phosphorylated tau) at higher levels (DE 992 μg PM/m³), suggesting that subchronic DE exposure may impinge on common neurodegenerative disease pathways. Together, these findings demonstrate that the brain’s immune system can detect and respond to DE and support that circulating cytokines may play a role in how neuroinflammation transfers to the brain. Further, these studies indicate that deleterious CNS effects may accumulate over-time to perturb neurodegenerative disease pathways, emphasizing the importance of further mechanistic inquiry.