Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo

Woodward, Nick; Levine, Morgan C.; Haghani, Amin; Shirmohammadi, Farimah; Saffari, Arian; Sioutas, Constantinos; Morgan, Todd E.; Finch, Caleb E.

doi:10.1186/s12974-017-0858-x

Cited by 116 publications

(98 citation statements)

References 66 publications

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“…Recently, studies evaluating the extensive toxicity mediated by air pollution, especially particulate matter (PM2.5), have shown that these particles via several different routes, including a direct way by inhalation or ingestion and indirect routes by systemic responses in the human body, reach the brain and then damage the parenchyma of the CNS through the blood–brain barrier (BBB) [ 29 , 30 ]. In the adult brain, PM2.5 passes through the BBB, inducing the inflammatory responses via (1) glial activation [ 31 , 32 , 33 ], (2) amyloid toxicity [ 34 , 35 ], and (3) altered expression of the glutamatergic pathway genes [ 25 , 36 ]. Many studies on air pollution have focused on the effects of inhaled pollution in the respiratory systems, especially on the nose and lungs.…”

Section: Discussionmentioning

confidence: 99%

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Kim

Shin

Han

et al. 2020

IJMS

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Air pollution has become one of the most serious issues for human health and has been shown to be particularly concerning for neural and cognitive health. Recent studies suggest that fine particulate matter of less than 2.5 (PM2.5), common in air pollution, can reach the brain, potentially resulting in the development and acceleration of various neurological disorders including Alzheimer’s disease, Parkinson’s disease, and other forms of dementia, but the underlying pathological mechanisms are not clear. Astaxanthin is a red-colored phytonutrient carotenoid that has been known for anti-inflammatory and neuroprotective effects. In this study, we demonstrated that exposure to PM2.5 increases the neuroinflammation, the expression of proinflammatory M1, and disease-associated microglia (DAM) signature markers in microglial cells, and that treatment with astaxanthin can prevent the neurotoxic effects of this exposure through anti-inflammatory properties. Diesel particulate matter (Sigma-Aldrich) was used as a fine particulate matter 2.5 in the present study. Cultured rat glial cells and BV-2 microglial cells were treated with various concentrations of PM2.5, and then the expression of various inflammatory mediators and signaling pathways were measured using qRT-PCR and Western blot. Astaxanthin was then added and assayed as above to evaluate its effects on microglial changes, inflammation, and toxicity induced by PM2.5. PM2.5 increased the production of nitric oxide and reactive oxygen species and upregulated the transcription of various proinflammatory markers including Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), triggering receptor expressed on myeloid cells 2 (TREM2), Toll-like receptor 2/4 (TLR2/4), and cyclooxygenase-2 (COX-2) in BV-2 microglial cells. However, the mRNA expression of IL-10 and arginase-1 decreased following PM2.5 treatment. PM2.5 treatment increased c-Jun N-terminal kinases (JNK) phosphorylation and decreased Akt phosphorylation. Astaxanthin attenuated these PM2.5-induced responses, reducing transcription of the proinflammatory markers iNOS and heme oxygenase-1 (HO-1), which prevented neuronal cell death. Our results indicate that PM2.5 exposure reformulates microglia via proinflammatory M1 and DAM phenotype, leading to neurotoxicity, and the fact that astaxanthin treatment can prevent neurotoxicity by inhibiting transition to the proinflammatory M1 and DAM phenotypes. These results demonstrate that PM2.5 exposure can induce brain damage through the change of proinflammatory M1 and DAM signatures in the microglial cells, as well as the fact that astaxanthin can have a potential beneficial effect on PM2.5 exposure of the brain.

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Section: Discussionmentioning

confidence: 99%

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Kim

Shin

Han

et al. 2020

IJMS

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“…Although autophagy may be involved in anti-inflammatory responses, autophagy may not play a significant role in LPS-induced inflammation since rafamycin treatment could improve pulmonary injury after LPS infection by down-regulating mTOR. As a result, there is a strong possibility of a signaling network between TLR4 and autophagy in the presence of PM-induced lung injury, with autophagy governed by a complex signaling network, and TLR4, a critical sensor of autophagy that is significantly involved in PM-induced immunity responses [36,37]. Since mTOR functions as a key autophagy checkpoint and is involved in PM-induced pulmonary inflammatory responses, it has been suggested that both the mTOR/autophagy and TLR4/MyD88 pathways affect lung injury [35].…”

Section: Discussionmentioning

confidence: 99%

“…Since mTOR functions as a key autophagy checkpoint and is involved in PM-induced pulmonary inflammatory responses, it has been suggested that both the mTOR/autophagy and TLR4/MyD88 pathways affect lung injury [35]. The TLR4-MyD88 pathway is considered an upstream signaling mediator of PM-induced pulmonary inflammatory responses, which induces the secretion or production of inflammatory cytokines and oxidants [36]. Oxidizing agents or other cytokines can inhibit mTOR activation, cause tissue cell autophagy, and lead to excessive inflammation and tissue damage [38].…”

Section: Discussionmentioning

confidence: 99%

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury

Lee

Baek

Kim

et al. 2020

IJMS

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The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.

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“…This technology allows for a more comprehensive analysis than the filterable (i.e. water extracted) particulate samples examined in our prior studies (Morgan et al, 2011;Saffari et al, 2015;Verma et al, 2009;Woodward et al, 2017a).…”

Section: Introductionmentioning

confidence: 99%

Diurnal variation in the proinflammatory activity of urban fine particulate matter (PM2.5) by in vitro assays

et al. 2018

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Background: Ambient particulate matter (PM) smaller than 2.5 µm in diameter (PM2.5) undergoes diurnal changes in chemical composition due to photochemical oxidation. In this study we examine the relationships between oxidative activity and inflammatory responses associated with these diurnal chemical changes. Because secondary PM contains a higher fraction of oxidized PM species, we hypothesized that PM2.5 collected during afternoon hours would induce a greater inflammatory response than primary, morning PM2.5. Methods: Time-integrated aqueous slurry samples of ambient PM2.5 were collected using a direct aerosol-into-liquid collection system during defined morning and afternoon time periods. PM2.5 samples were collected for 5 weeks in the late summer (August-September) of 2016 at a central Los Angeles site. Morning samples, largely consisting of fresh primary traffic emissions (primary PM), were collected from 6-9am (am-PM2.5), and afternoon samples were collected from 12-4pm (pm-PM2.5), when PM composition is dominated by products of photochemical oxidation (secondary PM). The two diurnally phased PM2.5 slurries (am- and pm-PM2.5) were characterized for chemical composition and BV-2 microglia were assayed in vitro for oxidative and inflammatory gene responses. Results: Contrary to expectations, the am-PM2.5 slurry had more proinflammatory activity than the pm-PM2.5 slurry as revealed by nitric oxide (NO) induction, as well as the upregulation of proinflammatory cytokines IL-1β, IL-6, and CCL2 (MCP-1), as assessed by messenger RNA production. Conclusions: The diurnal differences observed in this study may be in part attributed to the greater content of transition metals and water-insoluble organic carbon (WIOC) of am-PM2.5 (primary PM) vs. pm-PM2.5 (secondary PM), as these two classes of compounds can increase PM2.5 toxicity.

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Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo

Cited by 116 publications

References 66 publications

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury

Diurnal variation in the proinflammatory activity of urban fine particulate matter (PM2.5) by in vitro assays

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