The role of MAC1 in diesel exhaust particle‐induced microglial activation and loss of dopaminergic neuron function

Abstract

Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson’s disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22 µM; 50µg/mL), ultrafine carbon black (ufCB, 50µg/ml), or DEP extracts (eDEP; from 50 µg/ml DEP) and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced amoeboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pretreatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1−/− mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function.

Regulating the regulator of ROS production

“…The findings raise the intriguing question whether dysregulated ROS production during successive acute inflammatory events is conducive to the pathogenesis of autoimmune disorders. This concept also resonates with some earlier studies highlighting the effects of environmentinduced chronic systemic inflammation and the propensity of mammals to develop degenerative neurological disorders [2,3]. For example, it was observed that exacerbated NOX2 activity underlies microglia-mediated neurotoxicity that can lead to Parkinson's and Alzheimer's diseases [2].…”

“…This concept also resonates with some earlier studies highlighting the effects of environmentinduced chronic systemic inflammation and the propensity of mammals to develop degenerative neurological disorders [2,3]. For example, it was observed that exacerbated NOX2 activity underlies microglia-mediated neurotoxicity that can lead to Parkinson's and Alzheimer's diseases [2]. It was previously theorized that chronic low-grade inflammatory states promoted by exposure to environmental toxicants (air pollution, pesticides, etc.)…”

“…primes microglia (the macrophages of the brain) to produce exaggerated amounts of ROS generated largely by NOX2 [3]. As demonstrated by studies testing this hypothesis, microglia from animals exposed to diesel exhaust particles produced robust bursts of ROS when subsequently challenged with lipopolysaccharides [2]. Levels of ROS produced by primed microglia were demonstrated to be neurotoxic to dopaminergic neurons and induce npg neurodegeneration in a mouse model [4].…”

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].…”