Ambient urban dust particulate matter reduces pathologic T cells in the CNS and severity of EAE

O’Driscoll, Chelsea A.; Owens, L.; Hoffmann, Erica J.; Gallo, Madeline E.; Afrazi, Amin; Han, Mei; Fechner, John H.; Schauer, James J.; Bradfield, Christopher A.; Mezrich, Joshua D.

doi:10.1016/j.envres.2018.09.038

Cited by 22 publications

(19 citation statements)

References 59 publications

(83 reference statements)

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“…Previously our lab demonstrated that an intact standard ambient urban dust particle, SRM1649b PM, increased IL-17 and CYP1A1 mRNA in vivo and enhanced Th17 differentiation in an AHR-dependent manner measured by increased IL-17 mRNA and CYP1A1 mRNA as well as percent IL-17 positive cells in wild-type but not Ahr null cells in vitro [19]. More recently, we demonstrated that the intact SRM1649b PM enhanced Th17 differentiation in an AHR-dependent manner in vitro [26]. The chemically-extracted OF of SRM1649b PM also enhanced Th17 differentiation and increased CYP1A1 mRNA to the same extent as the intact PM suggesting the component of PM driving the responses was present in the OF [19].…”

Section: Resultsmentioning

confidence: 97%

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro

et al. 2018

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Atmospheric particulate matter (PM) is a complex component of air pollution that is a composed of inorganic and organic constituents. The chemically-extracted organic fraction (OF) of PM excludes inorganics but retains most organic constituents like polycyclic aromatic hydrocarbons (PAHs). PAHs are ubiquitous environmental toxicants and known aryl hydrocarbon receptor (AHR) ligands. The AHR is a ligand activated transcription factor that responds to endogenous ligands and exogenous ligands including PAHs. Activation of the AHR leads to upregulation of cytochrome P450 (CYP) metabolizing enzymes which are important for the biotransformation of toxicants to less toxic, or in the case of PAHs, more toxic intermediates. Additionally, the AHR plays an important role in balancing regulatory and effector T cell responses. This study aimed to determine whether PAHs present in PM aggravate inflammation by driving inflammatory T cell and dendritic cell (DC) responses and their mechanism of action. This study tests the hypothesis that PAHs present in PM activate the AHR and alter the immune balance shifting from regulation to inflammation. To test this, the effects of SRM1649b OF on T cell differentiation and DC function were measured in vitro. SRM1649b OF enhanced Th17 differentiation in an AHR and CYP-dependent manner and increased the percent of IFNγ positive DCs in an AHR-dependent manner. SRM1649b PAH mixtures enhanced Th17 differentiation in an AHR-dependent but CYP-independent manner and increased the percent of IFNγ positive DCs. Cumulatively, these results suggest that PAHs present in PM are active components that contribute to immune responses in both T cells and BMDCs through the AHR and CYP metabolism. Understanding the role of AHR and CYP metabolism of PAHs in immune cells after PM exposure will shed light on new targets that will shift the immune balance from inflammation to regulation.

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Section: Resultsmentioning

confidence: 97%

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro

et al. 2018

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“…SRM2975 synthetic PAH mixture enhanced Th17 differentiation only in the absence of CYP enzymes suggesting that the inhibition of CYP enzymes prevents the breakdown of the active component allowing for the observed T cell effect [(Figure 1 from O'Driscoll et al (100)] (100). Similarly, O'Driscoll et al (101) demonstrated that an ambient urban dust PM sample enhanced Th17 differentiation in an AHR-dependent manner. Likewise, Castaneda et al (64) showed that PM enhanced DC activation and primed naïve T cells toward a Th17-like phenotype in an AHR-dependent manner in vitro and in vivo .…”

Section: Particulate Mattermentioning

confidence: 89%

“…O'Driscoll et al (100) demonstrated that intranasal exposure to diesel PM samples, shown to enhance T cell differentiation through the AHR, worsened severity of EAE, however exposure to its chemically-extracted OF resulted in one diesel OF worsening severity of EAE but the other lost this effect. O'Driscoll et al (101) demonstrated that mice exposed intranasally to an ambient urban dust PM sample exhibited delayed disease onset and reduced severity of EAE and the delayed disease onset was AHR-dependent in vivo . Intranasal treatment to the ambient urban dust PM sample resulted in reduction of pathologic T cells in the CNS on day 10 after EAE induction and in a significant AHR-dependent reduction of IFNγ-producing T cells in an in vitro MOG-specific splenocyte assay (101).…”

Section: The Role Of Ahr In Autoimmune Diseasementioning

confidence: 99%

“…O'Driscoll et al (101) demonstrated that mice exposed intranasally to an ambient urban dust PM sample exhibited delayed disease onset and reduced severity of EAE and the delayed disease onset was AHR-dependent in vivo . Intranasal treatment to the ambient urban dust PM sample resulted in reduction of pathologic T cells in the CNS on day 10 after EAE induction and in a significant AHR-dependent reduction of IFNγ-producing T cells in an in vitro MOG-specific splenocyte assay (101). O'Driscoll et al (101) identified the AHR pathway as a novel pathway through with PM can reduce Th1 responses in the CNS and although this suppression of Th1 cells may reduce severity of disease it opens the door for opportunistic infection if the immunosuppression in non-reversible.…”

Section: The Role Of Ahr In Autoimmune Diseasementioning

confidence: 99%

“…Intranasal treatment to the ambient urban dust PM sample resulted in reduction of pathologic T cells in the CNS on day 10 after EAE induction and in a significant AHR-dependent reduction of IFNγ-producing T cells in an in vitro MOG-specific splenocyte assay (101). O'Driscoll et al (101) identified the AHR pathway as a novel pathway through with PM can reduce Th1 responses in the CNS and although this suppression of Th1 cells may reduce severity of disease it opens the door for opportunistic infection if the immunosuppression in non-reversible. In humans, Rothhammer et al (175) detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls.…”

Section: The Role Of Ahr In Autoimmune Diseasementioning

confidence: 99%

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The Aryl Hydrocarbon Receptor as an Immune-Modulator of Atmospheric Particulate Matter-Mediated Autoimmunity

O’Driscoll

Mezrich

2018

Front. Immunol.

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This review examines the current literature on the effects of atmospheric particulate matter (PM) on autoimmune disease and proposes a new role for the aryl hydrocarbon receptor (AHR) as a modulator of T cells in PM-mediated autoimmune disease. There is a significant body of literature regarding the strong epidemiologic correlations between PM exposures and worsened autoimmune diseases. Genetic predispositions account for 30% of all autoimmune disease leaving environmental factors as major contributors. Increases in incidence and prevalence of autoimmune disease have occurred concurrently with an increase in air pollution. Currently, atmospheric PM is considered to be the greatest environmental health risk worldwide. Atmospheric PM is a complex heterogeneous mixture composed of diverse adsorbed organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and dioxins, among others. Exposure to atmospheric PM has been shown to aggravate several autoimmune diseases. Despite strong correlations between exposure to atmospheric PM and worsened autoimmune disease, the mechanisms underlying aggravated disease are largely unknown. The AHR is a ligand activated transcription factor that responds to endogenous and exogenous ligands including toxicants present in PM, such as PAHs and dioxins. A few studies have investigated the effects of atmospheric PM on AHR activation and immune function and demonstrated that atmospheric PM can activate the AHR, change cytokine expression, and alter T cell differentiation. Several studies have found that the AHR modulates the balance between regulatory and effector T cell functions and drives T cell differentiation in vitro and in vivo using murine models of autoimmune disease. However, there are very few studies on the role of AHR in PM-mediated autoimmune disease. The AHR plays a critical role in the balance of effector and regulatory T cells and in autoimmune disease. With increased incidence and prevalence of autoimmune disease occurring concurrently with increases in air pollution, potential mechanisms that drive inflammatory and exacerbated disease need to be elucidated. This review focuses on the AHR as a potential mechanistic target for modulating T cell responses associated with PM-mediated autoimmune disease providing the most up-to-date literature on the role of AHR in autoreactive T cell function and autoimmune disease.

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Environmental Deterioration Due to Existing and Emerging Persistent Organic Pollutants: An Overview

Thilagam

Gopalakrishnan²

2021

Emerging Contaminants and Associated Treatment Technologies

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Ambient urban dust particulate matter reduces pathologic T cells in the CNS and severity of EAE

Cited by 22 publications

References 59 publications

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro

The Aryl Hydrocarbon Receptor as an Immune-Modulator of Atmospheric Particulate Matter-Mediated Autoimmunity

Environmental Deterioration Due to Existing and Emerging Persistent Organic Pollutants: An Overview

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