Diesel exhaust activates and primes microglia

Air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity

Shannon Levesque, Thomas Taetzsch, Melinda E. Lull, Urmila Kodavanti, Krisztian Stadler, Alison Wagner, Jo Anne Johnson, Laura Duke, Prasada Kodavanti, Michael J. Surace, Michelle Block

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. Objectives: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. Methods: Rats were exposed to DE (2.0, 0.5, and 0 mg/m 3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. Results: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL- 6 (interleukin- 6) protein, nitrated proteins, and IBA - 1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL 1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. Conclusions: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity.

Original languageEnglish (US)
Pages (from-to)1149-1155
Number of pages7
JournalEnvironmental Health Perspectives
Volume119
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

Fingerprint

Vehicle Emissions
Air Pollution
Microglia
Chemokine CX3CL1
Interleukin-6
Tumor Necrosis Factor-alpha
Brain
Inhalation
Macrophage Inflammatory Proteins
Proteins
Central Nervous System Diseases
Substantia Nigra
Mesencephalon
Interleukin-1
Chemokines
Neuroglia
Hydrogen Peroxide
Lipopolysaccharides
Nitric Oxide
1-(2-(dodecyloxy)ethyl)pyrrolidine hydrochloride

Keywords

  • Air pollution
  • Brain
  • Microglia
  • Neuroinflammation
  • Oxidative stress
  • Parkinson's disease

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

Diesel exhaust activates and primes microglia : Air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. / Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E.; Kodavanti, Urmila; Stadler, Krisztian; Wagner, Alison; Johnson, Jo Anne; Duke, Laura; Kodavanti, Prasada; Surace, Michael J.; Block, Michelle.

In: Environmental Health Perspectives, Vol. 119, No. 8, 08.2011, p. 1149-1155.

Research output: Contribution to journalArticle

Levesque, S, Taetzsch, T, Lull, ME, Kodavanti, U, Stadler, K, Wagner, A, Johnson, JA, Duke, L, Kodavanti, P, Surace, MJ & Block, M 2011, 'Diesel exhaust activates and primes microglia: Air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity', Environmental Health Perspectives, vol. 119, no. 8, pp. 1149-1155. https://doi.org/10.1289/ehp.1002986
Levesque, Shannon ; Taetzsch, Thomas ; Lull, Melinda E. ; Kodavanti, Urmila ; Stadler, Krisztian ; Wagner, Alison ; Johnson, Jo Anne ; Duke, Laura ; Kodavanti, Prasada ; Surace, Michael J. ; Block, Michelle. / Diesel exhaust activates and primes microglia : Air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. In: Environmental Health Perspectives. 2011 ; Vol. 119, No. 8. pp. 1149-1155.
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abstract = "Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. Objectives: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. Methods: Rats were exposed to DE (2.0, 0.5, and 0 mg/m 3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. Results: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL- 6 (interleukin- 6) protein, nitrated proteins, and IBA - 1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL 1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. Conclusions: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity.",
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AU - Kodavanti, Urmila

AU - Stadler, Krisztian

AU - Wagner, Alison

AU - Johnson, Jo Anne

AU - Duke, Laura

AU - Kodavanti, Prasada

AU - Surace, Michael J.

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N2 - Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. Objectives: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. Methods: Rats were exposed to DE (2.0, 0.5, and 0 mg/m 3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. Results: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL- 6 (interleukin- 6) protein, nitrated proteins, and IBA - 1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL 1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. Conclusions: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity.

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