Review

Air pollution: mechanisms of

neuroinflammation and CNS disease
Michelle L. Block1 and Lilian Calderón-Garcidueñas2,3
1
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA 23298, USA
2
Department of Biomedical and Pharmaceutical Sciences, College of Health Professions and Biomedical Sciences,
University of Montana, Missoula, Montana, USA
3
Instituto Nacional de Pediatria, Mexico City, Mexico

Air pollution has been implicated as a chronic source of discusses new mechanistic findings implicating innate
neuroinflammation and reactive oxygen species (ROS) immunity and chronic neuroinflammation in CNS damage
that produce neuropathology and central nervous sys- induced by air pollution.
tem (CNS) disease. Stroke incidence and Alzheimer’s
and Parkinson’s disease pathology are linked to air pol-
Air pollution defined
lution. Recent reports reveal that air pollution com-
Air pollution is comprised of a diverse mixture of particu-
ponents reach the brain; systemic effects that impact
late matter (PM), gases (e.g. ground-level ozone, carbon
lung and cardiovascular disease also impinge upon CNS
monoxide, sulfur oxides, nitrogen oxides), organic
health. While mechanisms driving air pollution-induced
compounds (e.g. polycyclic aromatic hydrocarbons and
CNS pathology are poorly understood, new evidence
endotoxins) and metals (e.g. vanadium, nickel, and
suggests that microglial activation and changes in the
manganese) present in outdoor and indoor air [5]. Of
blood–brain barrier are key components. Here we sum-
these components, PM and ground-level ozone are the
marize recent findings detailing the mechanisms
most widespread health threats and have been heavily
through which air pollution reaches the brain and acti-
implicated in disease [2,4]. In fact, millions of people in the
vates the resident innate immune response to become a
USA and around the world are chronically exposed to
chronic source of pro-inflammatory factors and ROS,
concentrations of air pollution above promulgated safety
culminating in CNS disease.
standards [5].
Inflammation is increasingly recognized as a causal factor PM is especially relevant for the CNS and is present in
in the pathology and chronic nature of central nervous urban air as a mixture of solid particles and liquid droplets
system (CNS) disease [1]. While diverse environmental suspended in air. The size of PM, from coarse wind-blown
factors have been implicated in neuroinflammation leading dust particles to ultrafine particles, contributes to their
to CNS pathology, air pollution may rank as the most biological effects. Ambient particles are characterized by
prevalent source of environmentally induced inflammation their sizes and aerodynamic properties: coarse particles
and oxidative stress [2]. Traditionally associated with with an aerodynamic diameter of 2.5 to 10 mm (PM10), fine
increased risk for pulmonary [3] and cardiovascular dis- particles of less than 2.5 mm (PM2.5), and ultrafine particu-
ease [4], air pollution is now also associated with CNS late matter (UFPM) of less than 0.1 mm. PM10 particles are
diseases including Alzheimer’s disease, Parkinson’s Dis- the respirable fraction originating from sources such as
ease, and stroke. road and agricultural dust, tire wear emissions, wood
Air pollution is a multifaceted environmental toxin that combustion, construction and demolition works, and
can assault the CNS through diverse pathways. Until mining operations [2]. PM2.5 are formed from gas
recently, the mechanisms underlying brain pathology and condensation of high temperature vapors during
induced by air pollution were unknown. However, despite combustion and industrial activities. Thus, PM2.5 are
the variable chemical and physical characteristics of air composed of both organic and inorganic compounds, in-
pollution and the consequent activation of multiple path- cluding sulfates, nitrates, carbon, ammonium, hydrogen
ways, inflammation and oxidative stress have been ident- ions, lipopolysaccharides (LPS), metals, and water [2],
ified as the common and basic mechanisms through which characteristics that contribute to their toxicity. Major
air pollution causes damage [4], including adverse effects sources of PM2.5 include oil refineries, metal processing
in the CNS. Furthermore, while multiple cell types in the facilities, tailpipe and brake emissions from mobile
brain are sensitive to air pollution, new reports indicate sources, residential fuel combustion, power plants, and
that microglia and brain capillaries may be the crucial wildfires [2]. However, UFPM is widely implicated in
factors responsible for cellular damage. This review PM-associated pathology because the nanometer size of
describes the complex composition of air pollution, the particles is most effective size for lung deposition,
explains current views on the multifaceted mechanisms penetration, and effects extending beyond the respiratory
through which air pollution impacts on the CNS, and tract [6–8]. Primary contributors to UFPM are tailpipe
emissions from mobile sources (motor vehicles, aircrafts,
Corresponding author: Block, M.L. (MBlock@vcu.edu). and marine vessels) [6]. Thus, PM is physically and
506 0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.05.009
Review Trends in Neurosciences Vol.32 No.9

chemically complex, making analyses of the biological more are exposed to PM occupationally and in disasters
effects of air pollution challenging. including war, fires, and in the aftermath of terrorist
The two fractions of PM predominantly implicated in attacks such as that on the World Trade Center [22].
CNS effects are PM2.5 and UFPM. Both are inhaled on a Diseases potentially affected by air pollution, including
regular basis due to air pollution, are acutely toxic to lung Alzheimer’s disease (AD) and Parkinson’s disease (PD),
and cardiovascular tissue [9], and cross the blood–air are also widespread. As the most prevalent neurodegen-
barrier of the lungs, gaining access to peripheral circula- erative disease [23], AD affects more than 4 million people
tion and the brain [6]. Indeed, increasing numbers of in the United States and an estimated 27 million world-
reports indicate that PM can enter the brain and may wide [24]. PD is a devastating movement disorder and the
be associated with neurodegenerative pathology in vivo second most prevalent neurodegenerative disease [23],
[10–14]. However, the mechanisms responsible for PM affecting 1–2% of the population over the age of 50 [25].
entry to the brain are a source of debate, where active Given these statistics it is of significant concern that recent
transport, a leaky blood–brain barrier, and translocation reports link air pollution to neuroinflammation and neu-
along the olfactory nerve into the olfactory bulb [15] have ropathology associated with both AD and PD.
been proposed. The first studies exploring this link were carried out on
Despite the complex composition of air pollution, classic animal (feral dog) populations naturally exposed to pol-
studies in the lung and cardiovascular system revealed luted urban environments [11]. Feral dogs living in regions
inflammation and oxidative stress as the common mech- of high pollution showed enhanced oxidative damage, pre-
anisms of air pollution-induced damage [3,4,6,9]. As dis- mature presence of diffuse amyloid plaques, and a signifi-
cussed in more detail below, not only do recent studies cant increase in DNA damage (apurinic/apyrimidinic sites)
indicate that inflammation and oxidative stress are com- in olfactory bulbs, frontal cortex, and hippocampus [11,12].
mon denominators in neuropathology and CNS disease [1], Further, dogs exposed to high concentrations of urban
but current reports also point to a growing chain of evi- pollution show tissue damage and accumulated metals
dence directly associating air pollution with CNS damage. (nickel and vanadium) at target brain regions in a gradient
fashion (olfactory mucosa > olfactory bulb > frontal cor-
Air pollution and CNS disease tex), implicating the nasal pathway as a key portal of entry
Ischemic stroke [11]. In a striking similarity, both AD and PD share early
While it is well-known that air pollution affects human pathology in the olfactory bulb, nuclei, and associated
health through cardiovascular and respiratory morbidity pathways, with olfactory deficits being one of the earliest
and mortality, it has only recently been shown that these findings in both diseases [26]. This work provided the first
deleterious effects extend to the brain. The impact of air association between exposure to pollution and acceleration
pollution upon the brain was first noted as an increase in of neurodegenerative disease pathology.
ischemic stroke in individuals exposed to indoor coal fumes These findings were recently confirmed and extended in
[16]. In the United States, stroke is the number one cause humans and other animal models. Brain tissue from indi-
of adult disability and the third most common cause of viduals residing in highly polluted areas showed an
death, behind only cancer and heart disease [17]. While increase in CD-68, CD-163, and HLA-DR positive cells
data on the association between cerebrovascular disease (indicating infiltrating monocytes or resident microglia
and ambient air pollution is limited, exposure to diverse air activation), elevated pro-inflammatory markers [interleu-
pollutants (e.g., particulate matter, ozone, carbon monox- kin-1b (IL1-b), cyclooxygenase 2 (COX2)], increased Ab42
ide, and nitrogen dioxide) is epidemiologically associated deposition (hallmark disease protein of Alzheimer’s dis-
with enhanced risk for ischemic cerebrovascular events ease), blood–brain barrier (BBB) damage, endothelial cell
[18–20]. In fact, current reports demonstrate that activation [27], and brain lesions in the prefrontal lobe [28].
enhanced risk for ischemic stroke correlates with air pol- Interestingly, upregulation of pro-inflammatory markers
lution, even in communities with relatively low pollutant such as COX2 and IL1-b, as well as the CD-14 marker for
concentrations [below current Environmental Protection innate immune cells, were localized in frontal cortex, sub-
Agency (EPA) safety standards] [19,21]. While the mech- stantia nigra and vagus nerves [27]. Further, animal stu-
anisms driving the pathology are unclear, ozone and dies revealed that air pollution causes cytokine production
particulate matter rapidly modulate the expression of [29,30], increases in MAP kinase signaling through JNK
genes involved in key vasoregulatory pathways in the [30], neurochemical changes [31], lipid peroxidation [32],
brain [10]. Current reports also indicate that the effects enhanced NFkb expression [29], and behavioral changes
of air pollution invade the brain parenchyma, causing [32]. Together, these studies clearly indicate that air pol-
pathology indicative of neurodegenerative disease. lution has CNS effects.
Abnormal filamentous protein aggregates and neuroin-
Air pollution and neurodegeneration flammation are common denominators of AD and PD [1].
Air pollution is a prevalent pro-inflammatory stimulus to While studies have yet to find a direct effect of air pollution
the CNS that has been largely overlooked as a risk factor on defined Lewy bodies (a pathological hallmark of PD) or
for neurodegenerative disease. In the United States alone, beta amyloid (Ab) plaques (a pathological hallmark of AD),
an estimated 29 million people are exposed to PM10, and 88 exposure to urban air pollution causes both neuroinflam-
million are exposed to PM2.5 [22]. Alarmingly, UFPM levels mation and accumulation of Ab42 (a component of Ab
are unmonitored and unregulated in the USA, but plaques) and a-synuclein (a component of Lewy Bodies)
exposure is estimated to be high. In addition, millions in target areas for AD and PD involvement [27]. For

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example, dogs exposed to high levels of air pollution show impact on peripheral innate immune cells, activate per-
deposits of diffuse amyloid plaques a decade earlier than ipheral neuronal afferents [47], and enter the brain
their clean air counterpart residents [11,12]. Further, the through diffusion and active transport to impact on the
accumulation of Ab42 and a-synuclein commences early in CNS [46]. In addition to cellular damage and modification
human childhood [27] following exposure to high concen- of the ROS/cytokine milieu in the brain, systemic inflam-
trations of air pollution, supporting the view that air mation alters the cellular make-up of innate immune cells
pollution may cause premature aging in the brain and/or in the brain. Specifically, in response to peripheral tumor
instigate disease processes early in development. One necrosis factor a (TNFa) injection, mice recruit larger
plausible mechanism is that nanoparticles [33–35] and amounts of circulating monocytes to the brain [45].
oxidative stress [36,37] modify the aggregation and rate Air pollution also causes pro-inflammatory signals
of protein fibrillation, potentially affecting soluble Ab and originating in peripheral tissues/organs including the lung
a-synuclein. It is possible that changes in protein aggrega- [48], liver [49], and the cardiovascular system [50], giving
tion associated with air pollution may mark early pathol- rise to a systemic-induced cytokine response [51] that
ogy in neurodegenerative disease processes. transfers inflammation to the brain [28,48,52]. Exposure
Environmental toxicants may exert their effects at to particulate matter elevates plasma cytokine concen-
multiple points across human development to culminate trations [IL-1b, interleukin-6 (IL-6), granulocyte-macro-
in CNS disease, a theory labeled ‘‘the multiple hit hypoth- phage colony-stimulating factor (GMCF)] that are
esis’’ [38]. Consistent with this premise, studies show that released into circulation as a consequence of interactions
PM impacts on the CNS early in childhood [28]. For between particles, alveolar macrophages, and airway epi-
example, MRI analyses revealed structural damage thelial cells [4]. Further, PM mobilizes bone marrow-
(hyperintense white matter lesions) localized to the pre- derived neutrophils and monocytes into the circulation
frontal cortex in children exposed to high concentrations of in both human and animal models [4]. Given these find-
air pollution, and potentially associated with cognitive ings, it is not suprising that air pollution is associated with
dysfunction [28]. Notably, dogs exposed to the same air neuroinflammation.
pollution also show frontal lesions with vascular/endo- Circulating cytokines produced in systemic inflam-
thelial pathology and neuroinflammation [28]. Thus, you- mation, such as TNFa and IL-1b, are well known to cause
ng humans and animals may be particularly vulnerable to neuroinflammation [53–56], neurotoxicity [53,55,56] and
the inflammatory effects of air pollution, and these effects cerebrovascular damage [57]. For example, chronic low-
may accumulate across an individual’s lifespan. grade inflammation associated with multiple systemic
While ischemic stroke [18–20], multiple sclerosis injections of low concentrations of lipopolysacharide
(exposure to second hand smoke promotes risk) [39], and (LPS), a cell wall component of gram negative bacteria
PD (manganese content in the air is linked to enhanced that is a potent pro-inflammatory stimulus, in adult mice
risk) [40] are currently the only CNS diseases with estab- results in mild neuroinflammation, rendering animals
lished epidemiological associations with air pollution more susceptible to further pro-inflammatory insult [55].
exposure, it is likely that many other uninvestigated dis- However, a single large pro-inflammatory insult in adult
eases have an even greater associated risk. These risks mice [i.e. one IP injection of a high concentration of LPS
may be distributed across individual differences in popu- (and TNFa injection)] results in chronic neuroinflamma-
lation susceptibility, as genetic predisposition may confer tion that persists for months after peripheral inflammation
vulnerability to the CNS effects of air pollution, such as is abates, leading to delayed and progressive neuron death
the case with inherited APOE4 allele carriers [27] in with onset only 7–10 months after LPS treatment [53].
humans and apoE knockout mice [41]. However, given Exposure to systemic inflammation early in development
the high prevalence of AD and PD, the link between can both cause and potentiate neuronal damage in adult
neuroinflammation and AD/PD pathogenesis, the estab- animals [56]. In addition to neuronal damage, systemic
lished CNS pathology caused by air pollution, and the inflammation caused by air pollution may contribute to
common high rate of human exposure to air pollution, deteriorating olfactory, respiratory, and blood–brain bar-
extending both mechanistic and epidemiological studies riers to enhance access to the CNS and further increase
to pursue the risks of other CNS diseases is of pressing neuropathology [11]. Thus, systemic inflammation caused
concern to human health. by air pollution is likely to give rise to both neuroinflam-
mation and neuropathology [13] where neurotoxic effects
Route of CNS effects may be cumulative.
Recent advances have provided key insights into how air
pollution exerts deleterious effects on the brain. Specifi- Particle effects: size matters
cally, cerebral vascular damage, neuroinflammation, and Ultrafine (nano-size particles) and fine particles are the
neurodegeneration in response to air pollution are believed most notorious air pollution components, penetrating lung
to occur through four major pathways (Figure 1). tissue compartments to reach the capillaries and circulat-
ing cells (e.g. erythrocytes) [7]. Experimentally, inhalation
Systemic inflammation: peripheral impact on the brain or nasal instillation of ultrafine particles in rodents results
Systemic inflammation is implicated in stroke [42,43], in the translocation of the particles into the systemic
neurodegenerative disease [44], and sickness behavior circulation [58] and the brain [15]. The nasal olfactory
[45,46]. The peripheral immune system communicates pathway is believed to be a key portal of entry, where
with the CNS through cytokines. Circulating cytokines inhaled nanoparticles reach trigeminal nerves, brainstem,

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Figure 1. Air pollution impacts on the brain through multiple pathways. Air pollution is a complex toxin that causes diverse CNS pathology through several interrelated
mechanisms that may lead to CNS disease. These effects can be categorized into four major groups: (i) systemic inflammation; (ii) particulate matter; (iii) adsorbed
compounds and (iv) ozone. While some CNS effects have been attributed to specific components of air pollution, no single clear pathway responsible for CNS damage has
yet been identified. In fact, due to the complex nature of this environmental toxin, it is likely that CNS pathology is due to the synergistic interactions 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.

and hippocampus [59,60]. Very recently, nano-sized confirm that inhalation of carbon black alone can cause
particulate matter was identified in the human brain inflammation [62], suggesting that something inherent in
[27]. Specifically, particulate matter has been observed the particle may be responsible. Indeed, UFPM exposure in
in human olfactory bulb periglomerular neurons, and mice induces the production of pro-inflammatory cytokines
particles smaller than 100 nm were observed in intralum- (IL1-b, TNFa, and IFNg) in the olfactory bulbs [63]. The
inal erythrocytes from frontal lobe and trigeminal ganglia inflammatory response to PM in both respiratory epithelial
capillaries [27]. These observations in highly exposed sub- cells [64,65] and microglia [66] (brain macrophages) relates
jects confirm that air pollution components reach the brain to physiochemical features of the particles such as surface
[13], and can penetrate deeply into the parenchyma. charge. Thus, particulate matter itself may indeed be pro-
However, once the particles reach the CNS, there is inflammatory once it reaches the brain.
considerable debate on the mechanisms of toxicity. Most
hypotheses are derived from traits conferred by the Adsorbed compounds: the Trojan Horse effect
physical and chemical constitution of the particulate mat- As mentioned previously, the particle components of air
ter. For example, ultrafine particles have a large surface- pollution have several toxic compounds present on their
to-volume ratio [8] and easily penetrate cell membranes surface (e.g. polyaromatic hydrocarbons) that vary accord-
[61]. This provides insights into why UFPM can traverses ing to the source of the PM, the geographic location of
traditional barriers in the lung and the BBB, and why PM sample collection, and season. Interestingly, nanoparticles
is found in neurons and is carried in erythrocytes. have been proposed as an ideal vehicle to enhance drug
Another hypothesis builds on the premise that the entry into the CNS [67]. Thus, particulate components of
particles themselves may stimulate innate immunity in air pollution may also represent an effective delivery sys-
the brain. Pattern recognition receptors are present on the tem for diverse environmental toxicants to the brain.
brain’s resident innate immune cells, microglia, and Additionally, some adsorbed compounds are soluble and
identify large pathogen-associated molecular patterns may become a toxic stimulus independent of the particle
such as charge and protein aggregates [1]. Studies exam- itself [13]. Indeed, the toxicity and immune-stimulating
ining the toxic effects of nanometer-sized carbon (carbon characteristics of particulate matter, such as diesel
black, a model of PM but without adsorbed compounds) exhaust particles (DEP) in the lung, have been linked to

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both the adsorbed chemicals on the outside of the carbon However, the specific signals from the lung to the brain
particle (e.g. transition metals and lipopolysaccharides) responsible for CNS pathology are unknown. While one
[6,9] and the physical characteristics of the particle itself hypothesis is that radical species generated in the lung
[68]. enter the blood and transfer to the brain [40], this seems
Many of the adsorbed compounds present in PM are unlikely due to the high reactivity and, again, the conse-
neurotoxic. For example, manganese is a component of quent short half-life of the radicals. Alternatively, alde-
urban air pollution, where concentrations in the air vary hyde ozone-lipid byproducts [40], ozone-modified soluble
based on location, season, and source [40]. Acute manga- proteins [40], activated circulating monocytes, or cytokines
nese exposure typically occurs as an occupational exposure from the pro-inflammatory lung response (systemic inflam-
in humans and is liked to dopaminergic neurotoxicity and mation) could exert harmful CNS effects. Interestingly,
PD symptoms [69]. Industrial activity is one source of systemic TNFa administration [81] causes lipid peroxi-
manganese in the air, and this can arise due to emissions dation in the brain, and TNFa is elevated in the brains
from ferroalloy production, iron and steel foundries, and of animals exposed to ozone [80], supporting the view that a
coke ovens. In addition, manganese is also dispersed as air cytokine could link a peripheral response to brain lipid
pollution due to gasoline engine combustion when the peroxidation, a noted effect of ozone administration in
gasoline contains methyclyclopentadienyl manganese animals. However, animal studies show that low ozone
tricarbonyl as an anti-knock agent [40]. Recently, both exposure fails to result in a systemic inflammatory
traffic- and environmentally-derived manganese in air response [82]. Further, ozone administration used as a
pollution was linked to increased risk for PD diagnosis treatment to attenuate pain in humans [83] and animals
[40,70]. We are only beginning to understand which of the [84] has variable results, suggesting that the concentration
factors present in air pollution play a central role in CNS and duration of ozone exposure may determine the nature
pathology. of its effects. Thus, while there is clear neuropathology, the
mechanisms through which ozone exerts toxic CNS effects
Ozone: inhalation of reactive oxygen species remain poorly understood.
Ozone is a major component of photochemical smog and
derives from multiple sources, including automobile Cellular mechanisms of neuroinflammation
exhaust. While ozone is not a radical, it is a reactive oxygen In addition to understanding how the effects of air pollu-
species and powerful inhaled oxidizing agent. Once in the tion reach the brain, recent studies have begun to address
lung, ozone interacts with proteins and lipids to create the cell types that mediate air pollution-induced CNS
modified proteins/lipids, carbon/oxygen centered radicals, pathology.
and toxic compounds [71]. For example, breakdown pro-
ducts from the interaction of ozone with lipids produce Astroglia
ozonides and cytotoxic aldehyde byproducts that are impli- Astroglia play essential roles in the integrity of the BBB,
cated in the extrapulmonary effects of ozone [71,72]. As a providing glia–neuron contact, maintaining ionic homeo-
consequence, ozone activates pulmonary macrophages, stasis, buffering excess neurotransmitters, and secreting
recruits neutrophils to the lung, and is linked to oxidative neurotrophic factors [85]. Astroglial activation occurs in
stress, airway inflammation, and dysfunction of innate response to all types of CNS injury [86]. Consistent with
immunity in the lung [73]. this, astroglia are reported to be activated in humans
Ozone is also associated with CNS effects. Recent stu- chronically exposed to high levels of air pollution, evi-
dies in animal models showed that oxidative stress induced denced by enhanced glial fibrillary acidic protein (GFAP)
by acute or chronic ozone exposure leads to brain lipid expression [14,27]. Animal studies investigating ozone
peroxidation [74,75], dopaminergic neuron death in the exposure showed that astrocytes localized near brain capil-
substantia nigra [76], neuronal morphological damage laries have enhanced expression of IL-6 and TNFa [80]. In
[76], motor deficits [75,77], and memory deficits [78]. addition, astrocyte exposure to ozone in vitro results in
Further, prenatal exposure to ozone alters neurotransmit- astrocyte death [87]. However, it is unclear how astroglia
ter expression in adult rats [79], suggesting an impact on in the brain are activated; in other words, whether the
CNS development. In addition, some ozone effects are astroglia respond to components of air pollution, to the
associated with the cerebral vasculature. For example, inflammation and oxidative stress produced from other cell
ozone exposure in adult rats causes cytokine production types, or to cellular damage.
in the brain, where enhanced IL-6 and TNFa expression
was localized to astrocytes close to capillary walls [80]. In Microglia
addition, ozone exposure upregulated expression of VEGF Microglia, the resident innate immune cells in the brain,
in rat brains, believed to be a compensatory and beneficial actively survey the brain environment [88] and are acti-
response [80]. Thus, there is increasing experimental evi- vated in neurodegenerative diseases such as AD and PD
dence that ozone causes neuroinflammation, lipid peroxi- [89]. In fact, human autopsy studies show evidence of
dation in the brain, neuronal damage, memory deficits, and increased CD14 expression [27] in response to chronic
motor deficits. exposure to high levels of air pollution, indicating upregu-
Because ozone is reactive with a short half-life, it is lation or activation of either infiltrating monocytes or the
unlikely to physically reach the brain, and molecules resident microglial cells. Microglia are activated in
derived from ozone and lung tissue interactions have been response to endogenous disease proteins (e.g. Ab and a
proposed to mediate non-pulmonary ozone effects [40,65]. synuclein), cytokines, neuronal death, and environmental

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toxicants (e.g. rotenone and paraquat) [1], including com- inflammatory factors (TNFa, PGE2, and IFNg) and oxi-
ponents of air pollution [90–92]. Microglia were first shown dative stress (NO, H2O2, O2 , ONOO /ONOOH) in the
to recognize and respond to PM in an in vitro study using brain, driving neurodegenerative diseases [1]. The chronic
diesel exhaust particles (DEP) [90]. Cultures treated with cycle of microglial activation in response to neuron damage
DEP showed microglial activation, as revealed by changes in is termed reactive microgliosis (Figure 2). Indeed, air
morphology and increased superoxide production, though pollution can contribute to toxic microglial activation by
TNFa, nitric oxide (NO), and PGE2 were not detected [90]. triggering the cycle of reactive microgliosis through three
Mixed neuron–glia cultures treated with DEP showed mechanisms: (i) components of air pollution may directly
selective dopaminergic neurotoxicity that only occurred activate microglia; (ii) cytokines from the peripheral
in the presence of microglia, indicating that microglia systemic inflammatory response may activate microglia;
mediate the neuronal damage [90]. Neuron-glia cultures (iii) particles, adsorbed compounds, or cytokines derived
derived from mice lacking functional NADPH oxidase, the from the periphery may directly damage neurons to acti-
enzyme responsible for microglial extracellular superoxide vate reactive microgliosis (Figure 2). Thus, air pollution
production, were insensitive to DEP-induced neurotoxicity, components may be misinterpreted as pathogens by micro-
indicating that microglia-derived ROS are crucial for glia, resulting in chronic inflammation, oxidative stress,
DEP-induced dopaminergic neurotoxicity [90]. Microglia neurotoxicity, and cerebral vascular damage.
are also reported to respond to titanium nanoparticles
by producing ROS [93] which is neurotoxic [66]. The blood–brain barrier
Interestingly, microglia exposed in vitro to concentrated Blood vessels throughout the body display a large range of
ambient air pollutants upregulate mRNA of pro-inflam- phenotypes differing in gross structure, function, cellular
matory cytokines, such as IL-1b and TNFa [91], suggesting ultrastructure, and blood–tissue exchange properties [97]
that some forms of PM induce cytokine production. that may result in unique responses to air pollution. When
Further, metals associated with air pollution activate compared to most peripherally located ‘‘leaky’’ vessels,
microglia, as microglia are activated in vitro by manganese cerebral microvessels (3–8 mm diameter) are distinct from
[94], a component of industrial-derived air pollution. most of the vasculature in that they are a formidable barrier
Microglial activation in response to manganese also ampli- to macromolecules, various toxins, small organic drugs, and
fies dopaminergic neurotoxicity in vitro [95]. In addition to ions [98]. Thus, these small vessels within the brain par-
neuronal death, disease proteins, and environmental trig- enchyma constitute the blood–brain barrier (BBB) [99]. The
gers such as air pollution, microglia are also activated by BBB is a chemical and physical barrier made up of multiple
cytokines produced in response to systemic inflammation, cell types, metabolizing enzymes, and transporter proteins
with disastrous neurotoxic consequences [53,56] (Figure 2), that protect the brain from external insult (Figure 3).
and cerebrovascular damage [96]. Particulate matter has been identified both in human
While the majority of microglial activation is beneficial, brain capillaries and in the brain parenchyma [27],
activated microglia can become a chronic source of pro- suggesting an ability to both interact with cells making

Figure 2. Chronic activation of microglia by air pollution. 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: (i) components of air pollution may directly activate
microglia; (ii) cytokines from the peripheral systemic inflammatory response may activate microglia; (iii) 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.

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Figure 3. Air pollution impacts the BBB at the cellular level. 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. (i) 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 (ii), evidence of endothelial cell damage (iii), and upregulation of VCAM/ICAM (iv) 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 (v),
which signal changes in transporter expression and function [e.g. P-glycoprotein (P-GP) and multidrug resistance associated protein-2 (MRP2)] (vi). 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.

up the BBB and to navigate across the BBB through yet Multidrug Resistance Associated Protein-2) and a decrease
unidentified mechanisms. Recent studies report that in expression of various tight junction proteins [101]. Thus,
aluminum nanoparticles can reduce human brain micro- brain capillaries recognize air pollution and respond to air
vascular endothelial cell viability, alter mitochondrial pollution components by regulating physical and chemical
potential, increase oxidative stress, and decrease tight barrier function and by producing pro-inflammatory sig-
junction protein expression, suggesting that nano-size nals. This response may serve as a pro-inflammatory
particles can injure endothelial cells and damage the sensor and ultimately distribute ROS, cytokines, and
BBB [100]. Human exposure to air pollution is associated particulate matter to the brain parenchyma, further con-
with endothelial cell damage in the cerebral vasculature, tributing to CNS pathology. In addition, these findings are
with increases in ICAM and VCAM [27]. In addition, in relevant to CNS pharmacotherapy in neurodegenerative
vitro studies using whole brain rat capillaries reveal that diseases. Specifically, the PM-induced upregulation of
treatment with particulate matter causes production of efflux transporters (P-glycoprotein and Multidrug Resist-
cytokines and ROS, and these signal changes in trans- ance Associated Protein-2) at the BBB may have signifi-
porter expression and function (e.g. P-glycoprotein and cant implications for drug availability in the brain

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Table 1. Research Overview: Effects of Air Pollution on the Brain

Air Pollution Experimental Neuroinflammation & Neuropathology & References
Model Model Pro-inflammatory Markers Behavior Changes
Particulate Matter Mouse N/T DA Neuron Damage in the 41
Substantia Nigra
Mouse IL1-b, TNFa, and INFg Change in 63
increase in Olfactory Bulb Neurotransmitters
Mouse Cytokine Production, JNK N/T 29,30
Activation, Enhanced NFkb
Expression
Mouse N/T Changes in 31
Neurotransmitters
Rat N/T Lipid Peroxidation, 32
Decrease in Exploratory
Behavior
Cell Culture Microglial Activation DA Neuron Damage 90
Superoxide Production
Cell Culture Microglial Activation N/T 91
TNFa & IL-6 Production
Brain Capillary TNFa & ROS P-GP & MRP2 Increase 101
Culture Production Tight Junction Protein
c-Jun Phosphorylation Decrease
Ozone Rat N/T Lipid Peroxidation 75-77
DA Neuron Damage &
Death in Substantia Nigra,
Motor Deficits
Rat N/T Lipid Peroxidation & 74,78
Impaired Memory
Rat Astrocyte IL-6 & TNFa Increase in Brainstem 80
Increase at BBB VEGF Expression
(Adaptive Repair
Response)
Prenatal Rat N/T DA, NA, DOPAC and HVA 79
Decrease
Cell Culture N/T Astrocyte Death 87
Nanoparticles Cell Culture Microglial Activation DA Neuron Damage 66,102
Superoxide Production
Cell Culture N/T HBMEC Toxicity, Lower 100
Tight Junction Expression
Mouse N/T Oxidative Stress (Brain) 103-105
Lipid Peroxidation
Chronic Human COX2, IL1-b, iNOS, & White Matter Lesions, 10,14,27,28,52,100
Ambient Air Pollution CD14 Increase Diffuse Ab Plaques,
a Synuclein Aggregation,
BBB Damage, Cognitive
Deficits, & DNA Damage
Dog iNOS, NFkb, & CD14 White Matter Lesions 11,12,28
Increase Diffuse Ab Plaques
a Synuclein Aggregation,
BBB Damage, & DNA
Damage
N/T, Not Tested; DA, Dopamine; IL-1b, Interleukin 1b; TNFa, Tumor Necrosis Factor a; INFg, Interferon g; JNK, c-Jun N terminal Kinase; NFkb, Nuclear Factor kb, IL-6,
Interleukin 6; ROS. Reactive Oxygen Species; PGP, P-Glycoprotein; MRP2 Multidrug Resistance Associated Protein-2; BBB, Blood Brain Barrier; VEGF, Vascular endothelial
growth factor; NA, norepinephrine; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; HBMEC, Human Brain Microvascular Endothelial Cells; COX2,
cycloxygenase 2.

parenchyma for individuals living in heavily polluted exposures. However, these crucial experimental studies
cities. have provided the foundation necessary to begin to
Together, animal, human, and cell culture studies have identify the CNS-toxic components of air pollution,
shown that air pollution causes CNS oxidative stress, providing an opportunity to address their role in CNS
neuroinflammation, neuronal damage, enhancement of disease, and paving the way for detailed experimental
abnormal filamentous proteins, BBB changes, and inquiry at the level of epidemiology.
cerebrovascular damage (Table 1), linking the pathways
through which air pollution impacts on CNS disease path- Summary and conclusions
ology. While the experimental evidence is compelling, In summary, air pollution is a complex mixture of environ-
given the chronic nature of human exposure to air pollu- mental toxicants that assault the CNS through several
tion, CNS effects are likely to reflect exposure over an cellular and molecular pathways to cause disease. CNS
entire human lifetime, including critical periods of effects are chronic, beginning in childhood, and may take
development. Notably, these chronic effects risk being time (years) to accumulate pathology. Specifically, air
overlooked by in vitro methods and in short term animal pollution causes neuroinflammation, oxidative stress,

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Acknowledgements
Genet. 16 (S2), R183–R194
This work was supported by the NIEHS/NIH Pathway to Independence
26 Doty, R.L. (2008) The olfactory vector hypothesis of
Award R00ES01549.
neurodegenerative disease: is it viable? Ann. Neurol. 63, 7–15
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