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Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity
Citation:
Levesque, S., T. Taetzsch, M. E. Lull, U. P. KODAVANTI, A. Wagner, J. Johnson, L. Duke, PRASADA RAO S. KODAVANTI, AND M. L. Block. Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 119(8):1149-1155, (2011).
Impact/Purpose:
The data show that diesel exhaust causes neuroinflammation through multiple pathways (i.e. systemic inflammation, particle characteristics, and absorbed compounds), activates microglia in vitro and in vivo, enhances inflammation-mediated DA neurotoxicity, and modulates brain fractalkine levels that protect against DE-induced DA neurotoxicity. This information is useful in understanding how neuronal tissues may also be a target for air pollution adverse effects. It supports the mode of action paradigm for adverse health effects of air pollutants.
Description:
Air pollution is linked to central nervous system (CNS) disease, but the mechanisms responsible are poorly understood. Rats exposed to Diesel Exhaust (DE, 2.0,0.5, and 0 mg/m3) by inhalation over 4 weeks demonstrated elevated levels of whole brain IL-6 protein, nitrated proteins, and IBA-1 protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFa, IL-1B, IL-6, MIP-1 a, RAGE, fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DE particles (DEP, 20 mg/kg) increased microglial ISA-1 staining and elevated both serum and brain TNFa at 6 hr post-treatment. Primary cultures exposed to nanometer-sized DEP <0.22 uM; 50ug/mL), ultrafine carbon black (ufCB, 50ug/ml), and DEP extracts (eDEP;from 50 ug/ml DEP), showed elevated IBA-1 staining, ameboid microglia morphology, H202 production, and microglia-mediated DA neurotoxicity in vitro. Microglia internalized DEP in vitro, which was blocked by the scavenger receptor inhibitor fucoidan without inhibiting H202 production. While DEP, eDEP, and ufCB alone failed to cause the production of cytokines and chemokines, DEP (5 ug/ml) pretreatment followed by LPS (2.5 ng/ml) in vitro synergistically amplified NO production, TNFa release, and DA neurotoxicity. Pre-treatment with fractaikine (50 pg/ml) in vitro ameliorated DEP (50ug/ml)-induced microglial H202 production and DA neurotoxicity. Together, these results demonstrate that DE causes neuroinflammation through multiple pathways (i.e. systemic inflammation, particle characteristics, and absorbed compounds), activates microglia in vitro and in vivo, enhances inflammation-mediated DA neurotoxicity, and modulates brain fractalkine levels that protect against DE-induced DA neurotoxicity. These findings provide much needed insight into the mechanisms through which air pollution exerts CNS effects and the potential etiology of Parkinson's disease.
