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

Abstract

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.

Keywords: T cells; aryl hydrocarbon receptor; atmospheric particulate matter; autoimmune disease; autoimmunity; polycyclic aromatic hydrocarbons.

Figure 1

Summary of the effects of DEP on T cells and autoimmune disease. This figure from O'Driscoll et al. (100) summarizes the differential effects of two DEPs, SRM1650b from a 4-cylinder diesel engine, and SRM2975 from a 2-cylinder diesel engine on T cell differentiation and autoimmune disease. SRM1650b enters the T cell, binds AHR, which then translocates to the nucleus and binds DNA, driving transcription of CYP enzymes (top). SRM1650b enhances Th17 differentiation in an AHR-dependent manner and worsens autoimmune disease (top). Based on the in vivo EAE data using the intact PM and chemically-extracted OF, SRM1650b requires the particle to aggravate autoimmune disease because of bioavailability of the PAHs and their ability to activate the AHR. Like SRM1650b, SRM2975 enters the T cell, binds AHR, translocates to the nucleus, binds DNA, and drives transcription of CYP enzymes (bottom). However, SRM2975 enhances Th1 differentiation in an AHR-dependent manner but still worsens autoimmune disease (bottom). Based on the in vivo EAE data demonstrating SRM2975 worsens autoimmune disease in PM and OF forms and the in vitro data showing a role of CYP enzymes in T cell differentiation, metabolism of SRM2975 plays a role in its ability to worsen autoimmune disease in that CYP metabolism of PAHs may lead to more potent intermediates that drive immune responses in vivo. Additionally, in the presence of PAHs and AHR activation, enhanced effector differentiation by both samples results in increase in Th17 or Th1 cells and a reduction in Treg cells. However, when PAHs are at much lower concentrations as with the low doses, enhanced effector differentiation is lost and Treg differentiation is enhanced. SRM, standard reference materials; DEPs, diesel exhaust particles; AHR, aryl hydrocarbon receptor; CYP, cytochrome P450; PAH, polycyclic aromatic hydrocarbons. This figure or a version of this figure was published in Particle and Fibre and Toxicology and is licensed under the Creative Commons Attribution 4.0 International Public License.

Figure 2

AHR signaling pathway. AHR is a ligand-activated transcription factor the resides in the cytosol being held in conformation by chaperone proteins until bound by ligand. Once bound by ligand, AHR translocates to the nucleus, sheds its chaperone proteins, and binds ARNT. This complex then binds XREs on DNA and induces gene transcription of genes such as CYP1A1. AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; XRE, xenobiotic response element; CYP, cytochrome P450.

Figure 3

Model of AHR modulation of PM-mediated autoimmunity. This figure is adapted from O'Driscoll et al. (100) and demonstrates how AHR may modulate PM-mediated autoimmunity. PM is inhaled by people and once inhaled is able to be taken-up and has the capacity to activate the AHR in cells within the body. AHR ligands, such as PAHs, adhered to atmospheric PM activate the AHR and cause the AHR to translocate to the nucleus and bind DNA elements such as XRE, inducing genes including CYP enzymes. The extent and duration of activation of AHR ligands shifts the immune balance enhancing effector T cells worsening autoimmunity or suppressing T cell responses and ameliorating autoimmunity. The AHR ligands adhered to the particulate have the potential to become bioavailable through metabolism or other mechanisms and then can be metabolized by CYP enzymes potentially causing other immune related effects or altering the immune responses. AHR, aryl hydrocarbon receptor; PM, particulate matter; PAHs, polycyclic aromatic hydrocarbons; XRE, xenobiotic response element; CYP, cytochrome P450. This figure or a version of this figure was published in Particle and Fibre and Toxicology and is licensed under the Creative Commons Attribution 4.0 International Public License.