NLRP3 Inflammasome: A Potential Therapeutic Target in Fine Particulate Matter-Induced Neuroinflammation in Alzheimer’s Disease

Abstract

As one of the most harmful air pollutants, fine particulate matter (PM2.5) has been implicated as a risk factor for multiple diseases, which has generated widespread public concern. Accordingly, a growing literature links PM2.5 exposure with Alzheimer’s disease (AD). A critical gap in our understanding of the adverse effects of PM2.5 on AD is the mechanism triggered by PM2.5 that contributes to disease progression. Recent evidence has demonstrated that PM2.5 can activate NLRP3 inflammasome-mediated neuroinflammation. In this review, we highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies to in-depth deciphering molecular mechanisms. First, neuropathological, epidemiological, and neuroimaging studies will be summarized. Then, the transport pathway for central nervous system delivery of PM2.5 will be presented. Finally, the role of NLRP3 inflammasome-mediated neuroinflammation in PM2.5 induced-effects on AD will be recapitulated.

Keywords

Alzheimer’s disease fine particulate matter microglia neuroinflammation NLRP3 inflammasome

INTRODUCTION

Since the London Great Smog of 1952, it has been suggested that air pollution is a significant risk factor with regard to public health. The ambient (outdoor) and household (indoor) air pollution has been associated with higher rates of premature death, morbidity, and disability-adjusted life-years [1]. Air pollution is a diverse mixture that includes particulate matter (PM), ozone, carbon monoxide, sulfur oxides, nitrogen oxides, methane, and other gases, volatile organic compounds (e.g., benzene, toluene, and xylene), and metals (e.g., lead, manganese, vanadium, iron) [2]. It is generated from numerous natural (e.g., forest fire or dust storms) and anthropogenic sources (e.g., traffic character, industry).

Among multiple air pollutants, fine particulate matter (PM2.5) has been regarded as one of the most harmful toxicants [3]. According to the data published by WHO, in 2016 about 4.2 million people suffered from air pollution, leading to shorter lifespan, which is mostly resulted from the PM2.5. Over the past few decades, a number of clinical and epidemiological studies have demonstrated the relationship between PM2.5 and multiple diseases, such as chronic obstructive pulmonary disease, ischemic heart disease, lung cancers, stroke, and neurodegeneration disease [1 , 5]. More recently, there is an increasing concern on the potential deleterious impact of PM2.5 exposure on Alzheimer’s disease (AD).

AD is the most common cause of dementia, which accounts for 60–70% of reported cases of dementia. According to the data published by WHO, AD represents the fifth leading cause of death all over the world in 2016. With the advance of social medical care, the lifespan of human beings has been significantly prolonged since the 20th century. Thus, the number of AD cases has been rising dramatically [6]. AD is clinically characterized by a progressive decline of cognitive function and pathologically characterized by the deposition of amyloid-β (Aβ) protein called senile plaques and aggregates of phosphorylated tau protein called neurofibrillary tangles [7]. The pathogenesis of AD has not yet been fully revealed. Multiple risk factors have been reported to contribute to the etiology of AD. Genetic factors are considered to be the main cause in about 70% of the overall risk, with the remaining 30% thought to be due to environmental factors (such as air pollution) and lifestyle (such as physical activity, smoking, alcohol) [8].

With this background, we aim to highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies to in-depth deciphering molecular mechanisms.

DEFINITION AND SOURCE OF PM2.5

Based on the predicted penetration capacity into a respiratory organism, PM can be defined by its aerodynamic diameter (coarse particulate matter (PM10) with an aerodynamic diameter of 10μm; fine particulate matter (PM2.5) with an aerodynamic diameter of 2.5μm) [9]. In particular, PM2.5 exerts a greater influence on human health than PM10 due to its capability of carrying diverse toxicants and its penetrability from the alveolar space to the circulatory system [10]. PM2.5 is complex mixture of organic and inorganic components. It not only contains a large amount of organic substances such as benzopyrene, polycyclic aromatic hydrocarbons (PAHs), nitro- and oxygenated-PAHs, but is also enriched inorganic chemicals such as sulfates, nitrates, and metals [9]. However, the composition, distribution, and concentration of PM2.5 varies, depending on environmental factors, such as different regions, different time periods (seasonal changes, days and nights), different weather conditions (wind speed and atmospheric humidity), and prevailing sources [1, 11]. For example, PM2.5 index in spring and winter is significantly higher than that in other seasons, as indicated from data in Taiyuan, Shanxi Province, China [12]. It might be ascribed to the coal combustion for heating demand of residents in winter [13]. The sources of PM2.5 include direct discharge into the atmosphere and conversion from gaseous precursors (such as sulfur dioxide, oxides of nitrogen, ammonia and non-methane volatile organic compounds) by natural and anthropogenic sources, the latter of which is the dominant source [14]. Natural source includes dust storms, forest fires, volcanoes, living vegetation, and sea spray [15]. On the other hand, anthropogenic sources include human combustion of solid-fuel (such as coal, lignite, heavy oil, and biomass), agricultural activities (such as burning of grass), industrial activities (such as smelting of metal), and erosion of the pavement by road traffic [16].

PM2.5 AND AD

Evidence from necropsy and autopsy studies

In 2002, a research group led by Lilian Calderón-Garcidueñas reported the first indirect evidence from a comparative necropsy study between healthy mongrel canine residents in Mexico City Metropolitan Area and those from Tlaxcala [17]. Mexico City Metropolitan Area was an urban area characterized by significant daily concentrations of pollutants, such as PM and other pollutants, while Tlaxcala with low levels of pollution represented controls. Healthy canines in Mexico City exhibited early and persistent activation of nuclear factor-kappa beta, inducible nitric oxide synthase, alterations in the blood-brain barrier (BBB) in cortical capillaries, degenerating cortical neurons, apoptotic glial white matter cells and deposition of apolipoprotein E-positive lipid droplets in smooth muscle cells and pericytes, non-neuritic plaques, and neurofibrillary tangles. The necropsy study on canine provided potential association between PM exposure and acceleration of AD pathology.

These findings were then confirmed and extended in autopsy studies on human individuals by the same group. Human residents in highly polluted areas indeed displayed an increased cyclooxygenase-2 (COX-2) expression in frontal cortex, hippocampus, and olfactory bulbs. Meanwhile, greater accumulation of neuronal and astrocytic Aβ₄₂ peptide was also detected [18]. Furthermore, brain tissue from individuals residing in highly polluted areas showed a significant increase in infiltrating monocytes or resident microglia activation (CD-68, CD-163, and HLA-DR positive cells), upregulated levels of pro-inflammatory markers (IL-1β, COX-2), increased Aβ₄₂ deposition, blood–brain barrier damage, and endothelial cell activation [19]. More importantly, children and young adults from exposed urbanites displayed significant upregulation of 134 genes (>2-fold). Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had Aβ plaques compared with 0% in controls [20]. The autopsy studies on human individuals further supported the potential role of PM exposure on AD pathology.

Necropsy and autopsy studies provided indirect link between air pollution and AD pathology. Furthermore, exposure to air pollution altered innate immune response and caused neuroinflammation in brain. As air pollution is a complex mixture, such as PM2.5, O3, and so on, it was hard to determine the role of PM (especially PM2.5) in the deleterious effects of long-term exposure on AD in human pathological studies. Fortunately, some animal studies provided evidence. A pilot study showed that 9-month PM2.5 exposure increased BACE protein levels, AβPP processing, and Aβ_1–40 levels. Meanwhile, a modest alteration in the cytokine profile was also detected [21]. Cacciottolo et al. found that a 15-week exposure to nPM increased amyloid plaques significantly more in mice carrying the human APOE ɛ4 gene than in mice carrying the human APOE ɛ3 gene [22]. Another study has found that exposure to ambient PM2.5 (3 mg/kg) for 4 weeks increased the level of tau hyperphosphorylation in 10-month-old mice [23].

Evidence from epidemiological studies

Considering that PM2.5 is known to exert harmful effects on health, researchers cannot assess the influence of PM2.5 on cognitive function by designing a clinical trial. Therefore, longitudinal observational studies may propose an appropriate option. Over the past decades, several studies have suggested a causal link between PM2.5 exposure and occurrence of cognitive decline or dementia.

The first epidemiological evidence was reported by Weuve et al. in 2012 [24]. The study population comprised the Nurses’ Health Study Cognitive Cohort, which enrolled 19,409 women aged 70 to 81 years [25]. The results suggested that higher levels of long-term exposure (7–14 years) to PM2.5 were associated with significant cognitive impairment. Cognitive decline by approximately 2 years was equivalent to that induced by a 10μg/m³ increment in long-term PM exposure [241]. In 2017, Chen et al. reported that PM2.5 exposure at the relative low levels was associated with higher dementia incidence in a Canadian population-based cohort study [26]. The results were verified by other studies [27 –30]. However, another study had yielded an inconsistent result. Loop et al. failed to demonstrate the association between PM2.5 exposure and incident cognitive impairment, even in participants with more than 12 months exposure [31]. It might be ascribed to the shorter exposure time. In 2019, Peters et al. systematically reviewed the epidemiological evidence with respect to the relationship between PM2.5 pollution and later cognitive decline and dementia until September 2018. The systematic review included 13 relevant papers, with studies from the USA (4 papers), Canada (2 papers), Taiwan (2 papers), Sweden (3 papers), and the UK (2 papers). The results indicated that PM2.5 exposure was significantly associated with increased risk of dementia [32]. The exposure time was varied in different studies. The threshold of exposure time for incident cognitive impairment was 4 years [32]. In a word, epidemiological studies indicated that PM2.5 exposure was significantly associated with occurrence of cognitive decline or dementia.

Impairment in episodic memory (e.g., the ability to remember past events, occurrences, and situations in the spatial and temporal context) is the hallmark symptom of AD, which is detectable in the early stage [33]. The Nurses’ Health Study reported no significant association between PM2.5 exposure and episodic memory decline in 2012 [25]. The Whitehall II study suggested a negative association between PM2.5 exposure and episodic memory decline in 2014 [27]. However, The Boston Puerto Rican Health Study indicated a positive association between PM2.5 exposure and episodic memory decline in 2018 [34]. There were significant discrepancies among the three cohort studies. One possible explanation was that only two to three cognitive assessments was performed in the three reports. Recently, the most compelling epidemiological study was published in the journal Brain [35]. A total of 998 female participants (aged 73 to 87 years) were included, who were enrolled in both the Women’s Health Initiative Study of Cognitive Aging and the Women’s Health Initiative Memory Study of Magnetic Resonance Imaging [36, 37]. All participants received annual (1999-2010) episodic memory assessment by the California Verbal Learning Test and two brain MRI scans (MRI-1:2005-06; MRI-2:2009-10). The results suggested that long-term PM2.5 exposure was associated with greater declines in episodic memory (immediate recall and new learning). Furthermore, the detrimental effect of PM2.5 exposure was equivalent to accelerated decline by approximately 4 years. These findings were observed even among cognitively normal older females. The study provided the first direct evidence that PM2.5 exposure accelerated episodic memory (the characteristic symptom of AD) in the preclinical stage.

In order to investigate the association between long-term exposure to PM2.5 and newly diagnosed AD, Jung et al. conducted a cohort study of 95,690 individuals in Taiwan during 2001–2010 [38]. The authors found that a 4.34 g/m³ increase in PM2.5 exposure led to a 138% increased risk of newly diagnosed AD. It suggested that long-term exposure to PM2.5 above the current US EPA standards were associated with increased incidence of AD. Furthermore, a systematic review and meta-analysis was performed to explore the effects of long-term exposure to PM2.5 on dementia/AD [39]. The authors analyzed the results of four cohort studies conducted in Canada, Taiwan, the UK, and the USA during 2015-2018 (N = 12,119,853). The results revealed that a 10μg/m³ increase in PM2.5 exposure was significantly and positively associated with dementia. In subgroup analyses, exposure to a 10μg/m³ increase in PM2.5 was found to be positively associated with AD. Hence, epidemiological studies have confirmed that PM2.5 exposure was significantly associated with a higher risk of AD.

Evidence from neuroimaging studies

In recent years, the effects of PM2.5 on brain structure have been investigated by MRI. Results from neuroimaging studies were inconsistent. However, some possible clues have been provided to understand the relationship between PM 2.5 exposure and AD.

The first neuroimaging evidence from an animal study was reported by Ejaz et al. in 2014 [40]. Wistar rats were exposed to PM for 4.5 months. However, neither alteration in the hyperintense signals nor any cortical atrophy of brain hemisphere was detected by T2-weighted imaging on MRI. As followed, several human studies investigated the effects of PM2.5 exposure on brain structure changes, such as brain volume and cerebrovascular injury.

In 2015, Framingham Offspring Study provided the first neuroimaging evidence for the association between PM2.5 exposure and brain structure in human [41]. The results suggested that higher exposure to PM2.5 (2μg/m³ increase) was associated with smaller total cerebral brain volume in the elderly. However, there was no significant association between PM2.5 and hippocampal volume. The above results were consistent with the Women’s Health Initiative Memory Study in older women [42]. Further, the Women’s Health Initiative Memory Study indicated that 3.49μg/m³ of cumulative PM2.5 exposure was associated with smaller white matter volume (6.23 cm³), but not grey matter volume. The smaller white matter volume was present in frontal and temporal lobes and corpus callosum. Hippocampal volume did not influence by PM2.5 exposure [42]. The association between increased PM2.5 exposure with smaller white matter volume in the elderly was confirmed by later studies [43, 44]. However, a voxel-based morphometry study suggested the association between increased PM2.5 exposure with smaller grey matter volume [44]. Interestingly, higher exposure to PM2.5 (5 mg/m³ increase) during fetal life was associated with thinner cortex in several brain regions of both hemispheres at 6 to 10 years of age [45]. Mortamais et al. also reported that prenatal exposure to PM2.5 might be associated with corpus callosum volume decrease in children aged 8–12 years [46]. Given the above, PM2.5 exposure (in the elderly or during fetal life) exerted a negative impact on brain volume (total brain volume or regional brain volume).

In addition, neuroimaging studies also explored the effects of PM2.5 on cerebrovascular injury. Framingham Offspring Study suggested that higher PM2.5 (2μg/m³ increase) was associated with 1.46 higher odds of covert brain infarcts in the elderly [41]. Wilker et al. reported no association between exposures to PM2.5 or residential proximity to major roads with increased burden of small vessel disease or neurodegeneration in the Massachusetts Alzheimer’s Disease Research Center Longitudinal Cohort [47]. Recently, a prospective cohort study in the journal Brain investigated the adverse effects of PM2.5 on the neuroanatomic structure using multilevel structural equation models approach [35]. The alteration of AD pattern similarity score (a structural brain MRI-based neuroanatomic biomarker reflecting high-dimensional grey matter atrophies in brain areas vulnerable to AD neuropathology) was evaluated across two time points (2005-06 and 2009-10) The results suggested that PM2.5-associated greater decline in episodic memory might be partly (10–22%) ascribed to increased AD pattern similarity score. In other words, the harmful effects of PM2.5 on episodic memory were mediated by progressive atrophy of grey matter, independent of cerebrovascular damage.

Hence, neuroimaging studies confirmed the detrimental effects of PM2.5 exposure on brain structure, especially on brain volume. In consideration of the discrepancies between published studies, the effects of PM2.5 on brain structure needed to be testified in more high-quality studies in the future.

In sum, the studies suggested the association between PM2.5 exposure and AD from the perspective of neuropathology, epidemiology, and neuroimaging. Furthermore, the link between PM2.5 exposure and neuroinflammation was also implied from the perspective of neuropathology.

TRANSPORT PATHWAY FOR CENTRAL NERVOUS SYSTEM DELIVERY OF PM2.5

There has been a tremendous interest in exploring the transport pathway for central nervous system delivery of PM2.5. Published researches implied two main routes: direct transport via the olfactory epithelium and systemic transport via the BBB.

Direct transport via the olfactory epithelium

In the early stages, the delivery of particles associated with PM to olfactory bulb was reported. Some metal particles (such as Mn, Ni, Zn, and so on) and non-metal particles (such as carbon) could reach olfactory neurons via the olfactory epithelium in the nasal cavity [48, 49]. Subsequent animal studies suggested that ultrafine PM deposited on the olfactory epithelium could translocated into brain through the olfactory neuronal pathway [40 –52]. More direct evidence arose from an autopsy study, which was performed in cases of sudden death. A research group led by Lilian Calderón-Garcidueñas reported that PM was seen in olfactory bulb neurons in residency in cities with high air pollution [19]. After entry to olfactory bulb, the distribution of PM occurred to the piriform cortex, olfactorytubercle, amygdala, and entorhinal cortex [53].

Indirect transport via the blood-brain barrier

In addition to the direct “nose-to-brain” pathway, traversing the BBB might be an indirect transport. As all known, intact BBB could protect the central nervous system from entry of various neurotoxicants. However, BBB was impaired in some conditions, such as age, infection, or toxicants [54]. A large number of studies have suggested that air pollutants disturbed the permeability of the BBB. Endothelial cell damage in the cerebral vasculature has been confirmed in residency in cities with high air pollution [19]. Chen et al. reported that manufactured aluminum oxide nanoparticles induced endothelial toxicity and affected the BBB [55]. In an in vitro study, PM2.5 damaged the tight junction of endothelial cells and increased permeability [56]. The results were consistent with other animal studies [57, 58]. A randomized crossover-controlled exposure study indicated that exposure to ambient coarse PM was associated with increased blood neural biomarkers that might indicate perturbations of BBB integrity [59]. Hence, PM2.5 was believed to disrupt BBB integrity and gain access to the central nervous system. Hartz et al. hypothesized that PM-induced systemic inflammation and oxidative stress resulted in the breakdown of the BBB [60].

PM2.5 AND INFLAMMATION

PM2.5 and systemic inflammation

For the past few years, growing attention has been paid to the role of systemic inflammation to help explain the effects of PM2.5 [61]. After long-term inhalation from the nasal cavity, PM2.5 could penetrate the alveoli. The deposition of PM2.5 in the alveoli caused lung inflammation. Exposure to PM2.5 resulted in an increase of proinflammatory gene and protein expressions in vitro [62, 63]. Furthermore, exposure to PM2.5 led to the infiltration of neutrophils and macrophages into the lung in vivo [62, 63]. Pulmonary inflammation allowed PM2.5 and inflammatory mediators pass through the gas-blood barrier into the bloodstream, which caused systemic inflammation. Systemic inflammation was also reported in other PM2.5 exposure related diseases, such as cardiovascular disease, chronic kidney disease, type 2 diabetes, bone diseases, systemic lupus erythematosus, and rheumatoid arthritis [1 , 64–67]. A massive amount of evidence demonstrated that PM2.5 exposure was associated with increased levels of proinflammatory mediators in the systemic circulation of both animals and humans [68]. A high-resolution metabolomics study further supported that the harmful effects of PM2.5 was mediated by systemic inflammation [69]. Moreover, a panel study among 40 healthy adults suggested that some special constituents (SO42–, Cl–, K+, and some elements) of PM2.5 might be responsible for systemic inflammation [70]. Further exploration suggested that the mechanisms of systemic inflammation included disruption of iron homeostasis and the aryl hydrocarbon receptor signaling pathways [67].

PM2.5 and neuroinflammation

In recent years, numerous studies have suggested that the detrimental effects of PM2.5 on brain might be partially ascribed to neuroinflammation. The hallmark of neuroinflammation was the activation of immune cells, such as microglia and astrocytes [71]. Animal experiments suggested that exposure to PM2.5 induced in astroglial and microglial activation in animal experiments [72, 73]. Campbell et al. reported that PM in polluted air triggered a proinflammatory response in mouse brain [74, 75]. PM2.5 exposure in utero promoted neuroinflammatory change in brains of adult mice [76]. Further studies implicated that microglia played a critical role in PM-induced neuroinflammation [77 –79]. In addition, an in vitro study indicated that PM2.5 upregulated the expression of inflammatory and innate immunity pathways in BV-2 microglial cells [80]. Liu et al. reported that supernatants collected from PM2.5-treated microglia decreased cell viability of primary neuronal cultures [56]. Traffic-related PM was proven to induce cytotoxicity, microglial activation and inflammation in BV-2 microglial cells [81]. Hence, PM triggered microglia-mediated neuroinflammation.

ROLE OF NLRP3 INFLAMMASOME-MEDIATED INFLAMMATION IN PM2.5-INDUCED EFFECTS ON AD

NLRP3 inflammasome-mediated neuroinflammation: A pivotal role in AD

Neuroinflammation has been regarded as a key mechanism in the pathogenesis of AD. As the first immune sentry, microglia clear Aβ plaques and release proinflammation cytokines, which eventually aggravate neuroinflammation [82]. Evidence from clinical and neuropathological researches have demonstrated that microglia-mediated neuroinflammation play a key role in the pathogenesis of AD [83]. Recent studies have begun to explore the detailed mechanism of microglia-mediated neuroinflammation in AD. Inflammasomes are intracellular multiprotein complexes in the cytoplasm, which represent platform for immune responses and regulate inflammation activation in innate immune [84]. As known, NLRP3 inflammasomes are the best characterized and most strongly associated with sterile inflammation [85]. NLRP3 comprises an N-terminal PYRIN domain (PYD), a central nucleotide-binding oligomerization domain (NACHT) and a C-terminal domain containing leucine-rich repeat (LRR) domain. Under various stimuli, NLRP3 oligomerizes via central NACHT domains and PYD is exposed. Then, the adaptor protein ASC is recruited through PYD-PYD homotypic interactions. Following that, ASC binds to caspase-1 via caspase activation and recruitment domain (CARD)-CARD interactions. Eventually, pro-caspase 1 is cleaved to active caspase 1 by autocatalysis, which leads to the maturation and release of IL-1β and IL-18. It has been demonstrated that NLRP3 inflammasome could be activated by a variety of PAMPs and DAMPs, such as a large number of pore-forming toxins, extracellular ATP, crystals, PM, Aβ, and other aggregates [86, 87]. To date, a two-signal model has been proposed for the activation of NLRP3 inflammasome. In detail, signal 1 (priming signal) is required for upregulating the transcription and expression of NLRP3 and pro-IL-1β, while signal 2 (activation signal) triggers assembly into the NLRP3 inflammasome complex [88].

The association between NLRP3 inflammasome and AD was first been demonstrated in 2008 [89]. Halle et al. found that NLRP3 inflammasome was demonstrated to be essential for the Aβ-induced caspase-1 activation, IL-1β release, and proinflammatory cytokines secretion in vitro. The results firstly suggested that NLRP3 inflammasome activation by Aβ was important for neuroinflammation in AD. An in vivo study demonstrated that NLRP3 inflammasome activation contributed to Aβ pathology, and suggested that NLRP3 inflammasome represented a new therapeutic target for AD [90]. Further study indicated that microglia-derived ASC specks played a key role in Aβ deposition and progression of AD, which supported the standpoint that inflammasome activation was linked to seeding and spreading of Aβ pathology in AD via prion-like cross-seeding [91]. In addition, the link between NLRP3 inflammasome activation and tau was explored. Stancu et al. reported that tau seeds activated NLRP3-ASC-dependent inflammasome in primary microglia and ASC deficiency significantly inhibited exogenously seeded tau pathology in tau transgenic mice [92]. Further study suggested that NLRP3 inflammasome loss-of-function reduced tau hyperphosphorylation and aggregation, and tau led to the activation of NLRP3 inflammasome. The results identified that NLRP3 inflammasome activation was important for tau pathology [93]. Hence, NLRP3 inflammasome played a pivotal role in crucial pathogenetic processes in AD, including Aβ pathology, tau pathology and neuroinflammation.

NLRP3 inflammasome: A promising target in PM2.5-induced systemic inflammation

In recent years, accumulating evidence has demonstrated that PM2.5-induced systemic inflammation might be mediated by NLRP3 inflammasome in multi-organ inflammatory disorders. Ogino et al. provided the first evidence that nasal inoculation of PM2.5 induced allergic airway inflammation by NLRP3 inflammasome-associated mechanism [94]. Further study suggested that PM2.5 could induce NLRP3 inflammasome activation through cathepsin B release, reactive oxygen species production, and potassium efflux, which eventually led to lung fibrosis [95]. A recent research implied that carbon black nanoparticle, a core constituent of PM2.5, induced pulmonary fibrosis partially through NLRP3 inflammasome activation [96]. The similar results have been proven in other organ systems, such as cardiovascular system and reproductive system. Jin et al. reported that PM2.5-induce cardiac inflammatory injury might be partly explained by the activation of NLRP3 inflammasome [97]. Furthermore, PM2.5-related cardiac injury is mediated by NLRP3 inflammasome activation in BALB/c mice and Apo E^–/– mice [98, 99]. Another study indicated that sperm quality decline induced by PM2.5 could be partly ascribed to the activation of NLRP3 inflammasome [100].

Inhibition of NLRP3 inflammasome attenuated PM2.5-induced systemic inflammation, which provided an insight into developing new therapeutics for PM2.5 exposure related diseases. 1,25-Dihydroxy vitamin D₃ reduced inflammation induced by PM2.5 via the p38/NF-κB/NLRP3 signaling pathway in human bronchial epithelial cells [101]. The protective effects of vitamin D₃ through NLRP3 inflammasome inhibition was also presented in PM2.5-induced tubule formation of human umbilical vein endothelial cells in vitro [102]. A967079 (transient receptor potential ankyrin 1 antagonist) alone, and combined with AMG9810 (transient receptor potential vanilloid 1 antagonist) reduced the activation of NLRP3 inflammasome in mice [103]. Trametes orientalis polysaccharide mitigated PM2.5-induced lung injury in mice partly via inhibition of NLRP3 inflammasome [104]. Resveratrol treatment alleviated PM-induced lung inflammation and fibrosis through inhibiting NLRP3 inflammasome activation [105]. A recent research suggested that miR-96 overexpression or FOXO3a suppression could partially rescue the fibrotic effects of carbon black nanoparticle (a core constituent of PM2.5) through inhibiting NLRP3 inflammasome [96].

NLRP3 inflammasome: A promising target in PM2.5-induced neuroinflammation in AD

In a recently published study, PM2.5 caused pathological injury and inflammation in the brain and intestine in AD transgenic mice. However, NLRP3 inflammasome-related inflammatory biomarkers was not detected. The authors speculated that the harmful effects of PM2.5 on brain might be associate with the changes in bacteria condition [106]. It was in consistent with the previous study, which showed that exposure to PM2.5 altered the composition of gut microbiota in a murine model [107]. Interestingly, the close crosstalk between NLRP3 inflammasome and microbiota-gut-brain axis has been proposed [108]. Shen et al. found that gut microbiota in AD patients could induce the activation of NLRP3 inflammasome in the intestinal tract of mice, subsequently causing the release of inflammatory factors [109]. Li et al. identified the bidirectional modulation between the gut microbiota and NLRP3 inflammasome in the progression of acute pancreatitis [110]. Together, we speculated that PM2.5 induced neuroinflammation through NLRP3 inflammasome in AD. Our previous research provided in vitro evidence for the speculation [111]. We found that PM2.5 exposure increased neuronal injury and inflammation in microglia under AD context. Firstly, we showed that PM2.5 exposure aggravated oligomeric Aβ-induced neuroinflammation and neuronal injury in neurons-microglia co-cultures via increasing IL-1β production. Secondly, we demonstrated that PM2.5-induced IL-1β production in oligomeric Aβ-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Thirdly, we demonstrated that NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures.

In order to further support the participation of NLRP3 inflammasome in PM2.5 associated development of AD, NLRP3 inflammasome inhibitors were used in vitro. We found that inhibition of NLRP3 inflammasome prevented PM2.5-induced neuronal injury and inflammation. Our research suggested that NLRP3 inflammasome might be a promising therapeutic target in alleviating the harmful health effects of PM2.5 exposure on AD [111]. However, no direct and causal evidence between PM2.5-induced NLRP3 inflammasome and AD has been demonstrated in AD transgenic models. In-depth exploration is needed in this setting.

CONCLUSIONS AND FUTURE RESEARCH DIRECTION

A number of studies have demonstrated the association between PM2.5 exposure and AD. The mechanisms through which PM2.5 increased the risk of AD are only beginning to be understood. Neuroinflammation plays a key role in the effects of PM2.5 on AD. Moreover, NLRP3 inflammasome-mediated neuroinflammation represents a possible new molecular mechanism. Hence, NLRP3 inflammasome may be a novel therapeutic target in alleviating the harmful health effects of PM2.5 exposure on AD. However, these initial findings are extremely incomplete. There are still many questions to be answered. Potential future directions to move this developing field forward are described below. Firstly, which components of PM2.5 are responsible for the neuroinflammatory effects in AD? Secondly, what are the pathways involved in the clearance of PM2.5 for brain under AD context? Thirdly, which receptors on microglia recognized PM2.5 and mediated the harmful effects of PM2.5 on AD? Lastly, how other cell types (such as astrocyte and oligodendrocyte) are reacted to PM2.5 in AD? Collectively, mechanistic understanding into the effects of PM2.5 contributes to the development of new therapeutic strategies for AD and the formulation of public health policy.

Footnotes

ACKNOWLEDGMENTS

We gratefully acknowledge funding support from National Natural Science Foundation of China (81500916, 81801298, 81271211, 81471215, 81870821), Youth Medical Talents Program of “Science and Education Strong Health Project” of Jiangsu Province (QNRC2016079, QNRC2016068), Medical Innovation Team Program of “Science and Education Strong Health Project” of Jiangsu Province (CXTDA2017030), Beijing Youth Talent Team Support Program (2018000021223TD08).

Authors’ disclosures available online ().

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