Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

Abstract

In addition to the well-established effects of air pollution on the cardiovascular and respiratory systems, emerging evidence has implicated it in inducing negative effects on the central nervous system. Diesel exhaust particulate matter (DEP), a major component of air pollution, is a complex mixture of numerous toxicants. Limited studies have shown that DEP-induced dopaminergic neuron dysfunction is mediated by microglia, the resident immune cells of the brain. Here we show that mouse microglia similarly mediate primary cerebellar granule neuron (CGN) death in vitro. While DEP (0, 25, 50, 100 µg/2 cm2) had no effect on CGN viability after 24 h of treatment, in the presence of primary cortical microglia neuronal cell death increased by 2–3-fold after co-treatment with DEP, suggesting that microglia are important contributors to DEP-induced CGN neurotoxicity. DEP (50 µg/2 cm2) treatment of primary microglia for 24 h resulted in morphological changes indicative of microglia activation, suggesting that DEP may induce the release of cytotoxic factors. Microglia-conditioned medium after 24 h treatment with DEP, was also toxic to CGNs. DEP caused a significant increase in reactive oxygen species in microglia, however, antioxidants failed to protect neurons from DEP/microglia-induced toxicity. DEP increased mRNA levels of the pro-inflammatory cytokines IL-6 and IL1-β, and the release of IL-6. The antibiotic minocycline (50 µM) and the peroxisome proliferator-activated receptor-γ agonist pioglitazone (50 µM) attenuated DEP-induced CGN death in the co-culture system. Microglia and CGNs from male mice appeared to be somewhat more susceptible to DEP neurotoxicity than cells from female mice possibly because of lower paraoxonase-2 expression. Together, these results suggest that microglia-induced neuroinflammation may play a critical role in modulating the effect of DEP on neuronal viability.

Neurotoxicity of traffic-related air pollution

“…As pointed out before, there is a strong convergence between human epidemiological studies and experimental animal studies with regard to both behavioral and biochemical end-points affected by such exposures (Costa et al 2014a). In addition, in vitro studies support in vivo observations by showing that DE-derived particles can activate microglia and induce oxidative stress and neuro-inflammation (Block et al 2004; Levesque et al 2011b; Roqué et al 2015; Roqué et al, unpublished). Exposure to high levels of air pollution, as common in several locations around the world, is troublesome (see Table 1 as example), in light of the suggested associations between exposure and neurodevelopmental and neurodegenerative diseases, such as autism or dementia.…”

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

“…Such effects have been found in vivo [35–39], and have been reproduced in vitro [117, 118]. For example, in the latter study [118] it was found that diesel exhaust particles activate microglia; microglia-generated oxidant species and pro-inflammatory cytokines such as IL-6 cause neuronal toxicity, which can be prevented by inhibiting microglia activation.…”

Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

“…Because the production of neuroinflammatory cytokines is one of the hallmarks of microglial activation, and ongoing in vitro studies in our laboratory indicate an important role for microglia in the mechanisms of toxicity of DE particles (Roqué et al, 2016), microglia activation upon DE exposure was also assessed. Figures 1 and 2 show that the expression of Iba1, a marker of microglia activation, is increased in both the olfactory bulb and the hippocampus.…”