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.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/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.

Air pollution, a rising environmental risk factor for cognition, neuroinflammation and neurodegeneration: The clinical impact on children and beyond

“…We are showing early AD and PD hallmarks in MCMA children and our findings are not isolated given that other authors are showing that the development of abnormal tau for example, starts in childhood [72,73]. Critical to our human studies, systemic inflammation, neuroinflammation and misfolded protein aggregates are progressive features elicited upon the administration of air pollutant components to experimental animals [52][53][54][74][75][76]. Our interpretation of AD and PD hallmarks in the setting of air pollution is on the side of initial protective responses [32,33].…”

“…Exposure to different size and composition PM is associated with production and deposit of misfolded protein aggregates (amyloid, alpha synuclein, hyperphosphorilated tau), oxidative stress, cell damage and death in susceptible neuronal populations [52][53][54].…”

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

“…Oppenheim et al (22) found that inhalation of vehicle emissions increased BBB permeability, and also increased levels of inducible nitric oxide synthase and IL-1β in the parenchyma. Neuroinflammation has been demonstrated in rodent models exposed to PM or gaseous pollutants (23,24); however, a mechanistic link between neuroinflammation and BBB permeability has not been established, and potential intermediate drivers of such effects remain unclear.…”

Associations of Traffic-Related Air Pollution with Children’s Attention Spans: a Factor Analysis

“…In-vivo studies in rats have indicated that subchronic diesel exhaust exposure causes neuroinflammation and elevated early markers of neurodegenerative disease [19]. Chronic respiratory tract inflammation may lead to brain inflammation by altering levels of circulating cytokines, such as TNF-α and IL-1.…”