Abstract
The aryl hydrocarbon receptor (AHR) has long been studied by toxicologists as a ligand-activated transcription factor that is activated by dioxin and other environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs). The hallmark of AHR activation is the upregulation of the cytochrome P450 enzymes that metabolize many of these toxic compounds. However, recent findings demonstrate that both exogenous and endogenous AHR ligands can alter innate and adaptive immune responses including effects on T-cell differentiation. Kynurenine, a tryptophan breakdown product, is one such endogenous ligand of the AHR. Expression of indoleamine 2,3-dioxygenase by dendritic cells causes accumulation of kynurenine and results in subsequent tolerogenic effects including increased regulatory T-cell activity. At the same time, PAHs found in pollution enhance Th17 differentiation in the lungs of exposed mice via the AHR. In this perspective, we will discuss the importance of the AHR in the immune system and the role this might play in normal physiology and response to disease.
Highlights
Our laboratory has been actively investigating the role of the aryl hydrocarbon receptor (AHR) in the immune system, and the variable effects seen after binding endogenous and exogenous ligands
Immunologists and those studying autoimmunity did not become interested in the AHR until 2008, when two high impact papers identified the role of the AHR in T-cell differentiation, with certain ligands enhancing Treg generation, and others enhancing Th17 differentiation, both in vitro and in vivo [8, 9]
We have recently shown that particulate matter (PM) in the form of urban dust particles (UDP) from the National Institute of Standards and Technology (NIST; SRM1649b), containing polycyclic aromatic hydrocarbons (PAHs), increases the Th17 response both in the lung in vivo and in T-cells in vitro [29]
Summary
Our laboratory has been actively investigating the role of the aryl hydrocarbon receptor (AHR) in the immune system, and the variable effects seen after binding endogenous and exogenous ligands. This relationship of the AHR with the immune system, where binding of this receptor with different ligands in differing milieus can lead to seemingly opposing responses in T-cell differentiation has allowed us to come up with the following hypothesis: THE AHR AS A SENSOR The AHR serves as a sensor that responds to signals, both from the outside environment or internal milieu, to modulate an immune response.
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