Sustained exposure to significant levels of airborne UFPs, PM, and LPS may result in the direct translocation of these pollutants to the CNS where they can result in neuropathology through a variety of pathways and mechanisms (). Alternatively, air pollutants might not enter the CNS directly, but could exert adverse effect on the CNS by triggering the release of soluble inflammatory mediators from primary entry organs or secondary deposition sites. The release of inflammatory agents could then lead to or alter the susceptibility for neuroinflammation and neurodegeneration in the CNS.
The impact of air pollution on the brain through multiple pathways.
Once taken up by the body, fine PM or NPs could rapidly enter the circulatory system with the potential to directly affect the vascular system. For instance, NPs could be inhaled and cross the alveolar-capillary barrier in the lungs. The ability of NPs to cross this barrier is influenced by a number of factors that include the size of the particles, their charge, their chemical composition as well as their propensity to form aggregates. Even though the translocation of inhaled or instilled NPs across the alveolar-capillary barrier has been clearly demonstrated in animal studies for a range of NPs [23
], it has been more difficult to directly demonstrate this mechanism in humans [3
Regardless of the route of entry, NPs that reach the circulation could directly affect vascular endothelium cells by creating local oxidative stress or by causing proinflammatory effects similar to those seen in lung tissue. Inflammatory mediators that are produced in the respiratory tract as a consequence of chronic pollutant-induced epithelial and endothelial injury can lead to systemic inflammation [25
]. The systemic inflammation is accompanied by the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα
), interleukin-6 (IL-6), and interleukin-1beta (IL-1β
), for which blood vessels in the brain exhibit constitutive and induced expression of receptors [1
]. The cytokines could thus activate cerebral endothelial cells, disrupt the blood-brain barrier (BBB) integrity, or trigger signaling cascades that lead to the activation of mitogen-activated protein (MAP) kinase, and nuclear factor kappa B (NFκ
B) transcription factor-mediated pathways. Disruption of the BBB could then be followed by trafficking of mast cells and inflammatory cells expressing CD163, CD68, and HLA-DR to the damaged site [10
]. In addition, circulating cytokines that are released by inflamed peripheral organs or endothelial cells could stimulate peripheral innate immune cells, activate peripheral neuronal afferents, or enter the brain by diffusion and active transport thereby worsening the condition synergistically [27
]. Accordingly, brain tissue samples from individuals residing in highly polluted areas show an increase in the number of infiltrating monocytes or activated microglia, increased expression of IL-1β
, BBB damage, endothelial cell activation, and brain lesions in the prefrontal lobe [10
Airborne LPSs may induce neuroinflammatory responses directly by activating the brain's innate immune system. The effect of LPS on neuroinflammation is well studied in a bacterial endotoxin/LPS-based experimental model of PD that constitutes an important tool to delineate the mechanisms of neuroinflammation-mediated loss of dopaminergic neurons [29
]. This system could also be exploited in combination with exposure to other environmental toxins and air pollutants. Brain uptake of circulating LPSs is usually low, and most effects of peripherally administered LPS are likely to be mediated through LPS receptors located outside the BBB [30
]. Thus, LPSs might stimulate afferent nerves, act at circumventricular organs, or alter the permeability of the BBB. Circumventricular organs are specialized brain structures located around the third and fourth ventricle. They are highly vascularised and lack a BBB; therefore, they allow for a direct uptake of chemicals circulating in the blood stream by neuronal cells [31
The very small UFPs on the other hand easily penetrate cell membranes because of their large surface-to-volume ratio, which also enables them to traverse the classical barriers in the lung and the brain. Their ability to cross cell membranes easily explains why PM can be found inside neurons or erythrocytes [1
]. It has also been proposed that the close contact between endothelial cells and erythrocytes could represent a route for the exchange of PM between activated endothelial cells and UFP-loaded erythrocytes [1
Another important and more direct route for UFPs to enter the nervous system is through the olfactory mucosa, which is a neuronal epithelium that is in direct contact with the environmental air [35
]. Thus, fine and UFPs may reach the brain through olfactory receptor neurons or the trigeminal nerve. Olfactory receptor neurons are bipolar sensory neurons that mediate the sense of smell by conveying sensory information from the nose to the CNS. The olfactory epithelium is covered by a layer of sustentacular cells, but olfactory sensory neurons extend their dendrites into the mucous layer covering the olfactory epithelium where they directly interact with odorants inhaled with the air. Nasally inhaled pollutants that reach the olfactory mucosa could enter the cilia of olfactory receptor neurons by pinocytosis, simple diffusion, or receptor-mediated endocytosis. Once incorporated into sensory neurons, they could be transported by slow axonal transport along the axons to the olfactory bulb [38
]. From there, pollutants could be transported further into the CNS along mitral cell axons that project from the olfactory bulb to multiple brain regions, including the olfactory cortex, the anterior olfactory nucleus, the piriform cortex, the amygdale, and the hypothalamus.
Accordingly, UFPs have been observed in human olfactory bulb periglomerular neurons and trigeminal ganglia capillaries [10
]. Similarly, a decreasing gradient of metal (vanadium and nickel) deposition and accompanying tissue damage from the nose to the brain has been reported in the canine nervous system, confirming the importance of the nasal route for the entry of air pollutants into the CNS [39
]. Controlled exposures of rats to UFPs and metals also demonstrated their accumulation in the olfactory bulb [40
]. Taken together, these findings suggest that NPs can be taken up directly by the olfactory mucosa and enter the CNS or the cerebrospinal fluid by bypassing the circulatory system [12
]. Uptake through the nose might even be enhanced by additional pollutant-induced systemic inflammation by deteriorating the olfactory mucosal barrier, which would result in increased neuropathology.
Additional direct neuronal entry routes for NPs have been described that involve the retrograde and anterograde transport in axons and dendrites such as the transport of inhaled NPs to the CNS via sensory nerve fibers that innervate the airway epithelia [12
]. Ground-level ozone exposure activates the CNS through the vagal nerves without the involvement of the thoracic spinal nerves [43
]. PM-related LPS is likely to play an important role in these pathways, as shown by vagal upregulation of CD14 [44
Even though the translocation rate of NPs from their site of entry to secondary organs might be rather low, continuous or chronic exposure to NPs may result in their accumulations in the brain as a secondary target organ in significant amounts [12
]. Thus, it is also important to obtain data on the retention characteristics of NPs in both primary and secondary target organs, including associated elimination and clearance pathways [12
]. With regard to the CNS, no data on NP elimination are available yet. It is conceivable, however, that CSF circulation provides an excretory pathway for NPs that enter via neuronal uptake. Usually, the CSF serves as a fluid cushion for the brain, but also distributes substances to all brain regions and acts as an elimination route for metabolic waste products [45
]. NPs could be eliminated from the CSF through the same mechanisms: uptake of CSF by the blood circulatory system through arachnoid vili or via the nasal lymphatic system. The exact details of NP clearance from the brain, however, await future investigation [12