Microglia can become toxically activated by either pro-inflammatory stimuli or in response to neuronal damage. Regardless of how the neuron is damaged, microglia respond to form a chronic cycle of toxic microglial activation called reactive microgliosis. Indeed, air pollution can contribute to toxic microglial activation by triggering the cycle of reactive microgliosis through three mechanisms: 1) components of air pollution may directly activate microglia; 2) cytokines from the peripheral systemic inflammatory response may activate microglia; 3) particles, adsorbed compounds, or cytokines derived from the periphery may directly damage neurons to activate reactive microgliosis. Thus, air pollution components trigger reactive microgliosis at multiple points in the cycle to result in neuronal damage. Black dots depict particulate matter.

Air pollution is a complex toxin causing diverse CNS pathology through several interrelated mechanisms that may lead to CNS disease. These effects can be categorized into four major groups: 1) Systemic inflammation; 2) Particulate matter; 3) Adsorbed compounds; 4) Ozone. While some CNS effects have been attributed to specific components of air pollution, a single clear pathway responsible for CNS damage has yet to be identified. In fact, due to the complex nature of this environmental toxin it is very likely that CNS pathology is due to the synergistic interaction of the multiple pathways listed here, making air pollution a potent, biologically relevant environmental exposure and a significant challenge for mechanistic inquiry. Black dots depict particulate matter.

Brain capillaries form a chemical and physical barrier comprised of multiple cell types, metabolizing enzymes and transporter proteins, protecting the brain from external insult. The circumference of the capillary lumen is surrounded by a single endothelial cell (EC) and the opposing membranes are sealed by tight junctions (TJ). Pericytes (PC) are attached to the abluminal surface of the EC and are thought to regulate BBB function. The basal lamina (BL) is contiguous with the plasma membranes of astrocyte end-feet (AEF) surrounding both the PC and the EC. Black dots depict particulate matter. Chronic exposure to air pollution results in an increase in peripheral circulating cytokines and particulate matter (the particle components of air pollution). Upon chronic exposure to high levels of air pollution, there is a decrease in tight junction proteins, evidence of endothelial cell damage, and upregulation of VCAM/ICAM in the cerebral vasculature, suggesting potential failure of the physical barrier. In addition, particulate matter causes production of cytokines and reactive oxygen species (ROS) in brain capillaries, which signal changes in transporter expression and function (e.g. P-glycoprotein, P-GP and Multidrug Resistance Associated Protein-2, MRP2) and a decrease in expression of various tight junction proteins. Thus, brain capillaries recognize air pollution and respond by regulating the physical and chemical barrier function and producing pro-inflammatory signals. In addition, this response may serve as a pro-inflammatory sensor and ultimately distribute ROS, cytokines, and particulate matter to the brain parenchyma, further contributing to CNS pathology.