title: Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity.
abstract: BACKGROUND
  Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood.
  
  
  OBJECTIVE
  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/m3) 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.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Levesque
authors.forename: Thomas
authors.initials: T
authors.lastname: Taetzsch
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Lull
authors.forename: Urmila
authors.initials: U
authors.lastname: Kodavanti
authors.forename: Krisztian
authors.initials: K
authors.lastname: Stadler
authors.forename: Alison
authors.initials: A
authors.lastname: Wagner
authors.forename: Jo Anne
authors.initials: JA
authors.lastname: Johnson
authors.forename: Laura
authors.initials: L
authors.lastname: Duke
authors.forename: Prasada
authors.initials: P
authors.lastname: Kodavanti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Surace
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
mesh_terms: D000397:Air Pollution / Q000009:adverse effects*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054405:Chemokine CCL3; D054428:Chemokine CX3CL1 / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D054405:Chemokine CCL3; D054428:Chemokine CX3CL1; D053583:Interleukin-1beta; D015850:Interleukin-6; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; D001335:Vehicle Emissions; D006861:Hydrogen Peroxide