Mixed Metal Components in PM Contribute to Chemokine Receptor CCR5-Mediated Neuroinflammation and Neuropathological Changes in the Mouse Olfactory Bulb.

Particulate matter, especially PM, can invade the central nervous system (CNS) the olfactory pathway to induce neurotoxicity. The olfactory bulb (OB) is the key component integrating immunoprotection and olfaction processing and is necessarily involved in the relevant CNS health outcomes. Here we show that a microglial chemokine receptor, CCR5, is the target of environmentally relevant PM in the OB to trigger neuroinflammation and then neuropathological injuries. Mechanistically, PM-induced CCR5 upregulation results in the pro-inflammatory paradigm of microglial activation, which subsequently activates TLR4-NF-κB neuroinflammation signaling and induces neuropathological changes that are closely related to neurodegenerative disorders (, Aβ deposition and disruption of the blood-brain barrier). We specifically highlight that manganese and lead in PM are the main contributors to CCR5-mediated microglial activation and neuroinflammation in synergy with aluminum. Our results uncover a possible pathway of PM-induced neuroinflammation and identify the principal neurotoxic components, which can provide new insight into efficiently diminishing the adverse health effects of PM.