Trends in Immunology
ReviewAutoimmunity and the environmentThe aryl hydrocarbon receptor in immunity
Introduction
The incidence of autoimmune and allergic diseases in the developed world has been increasing over the last few decades and a growing body of evidence indicates that chemicals of low molecular weight (<1000 Da) are an important contributor to this phenomenon. Polycyclic aromatic compounds, which are formed during the combustion of organic materials and are therefore found in cigarette smoke, wood smoke and automobile exhaust gases, are increasingly linked to immune-related diseases. Such low-molecular-weight chemicals are also ubiquitous as food components, in life-style products (e.g. cosmetics) and as environmental pollutants. They can form protein adducts and haptenize antigens, expose cryptic antigens and act as endocrine disruptors. The immune system in turn responds to neo-antigens generated by small chemicals. Small chemicals can also take part in normal immunological differentiation and signaling pathways, with glucocorticoids a well-known example. Immunotoxicology occurs via adverse interference by small chemical xenobiotics with the immune system, such as allergic reactions to urushiol (the active ingredient of poison ivy), drug-induced autoimmunity, or immunosuppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to as dioxin hereafter). Moreover, immunopharmacologists are interested in small chemicals in their search for immunomodulating compounds that could be used to mimic or specifically block immune functions.
The transcription factor aryl hydrocarbon receptor (AhR) is a cytosolic sensor of small synthetic compounds (called xenobiotics by toxicologists) and natural chemicals, which act as its ligands (also called agonists). Ligand binding induces a conformational change in AhR, thereby exposing a nuclear translocation site. Ligands can be of diverse chemical structure and need to meet only minimal requirements for size and planar shape. AhR is chaperoned by heat shock protein 90, p23 and AhR-interacting protein in the cytosol. Both allele and species differences account for the range of AhR ligand affinities, which can differ by orders of magnitudes (Box 1). AhR was first discovered as a mediator of dioxin toxicity, including immunotoxicity. Persistent triggering of AhR results in other pathological effects in both animals and humans 1, 2.
AhR is highly conserved in evolution and is present in many cell types, albeit at differing abundance 3, 4, 5. The selective forces that led to the high degree of conservation of the AhR amino acid sequence are unknown and its physiological function(s) are still being elucidated. At present, it is clear that AhR has a dual role as an activator of metabolism of small molecules and as a player in many cell functions, including the immune system. As discussed below, AhR might link adaptive immune responses to environmental factors. AhR null mutant mice, mice with a constitutively active AhR and several other mutants of the AhR signaling pathway have been generated and used to analyze the physiological function of AhR, including its role in the developing immune system [6]. In parallel, endogenous and/or exogenous natural AhR ligands – long enigmatic – have been discovered, providing important insights into the physiological functions of AhR. In this review we consider AhR signaling, the endogenous low-molecular-weight chemicals that trigger it and its effects on natural immunological function(s). In particular we focus on the role of AhR in T-cell biology and its suggested link to autoimmune diseases.
Section snippets
Brief overview of the biochemistry of AhR signaling
AhR is a member of the bHLH-PAS protein family found in organisms as diverse as Caenorhabditis elegans (nematode), Drosophila melanogaster (insect) and mammals [3]. bHLH-PAS proteins are biological sensors for a variety of stimuli, controlling neurogenesis, vascularization, circadian rhythms, metabolism and stress responses to hypoxia, among others.
During canonical signaling, cytosolic AhR binds to a suitable small chemical (the ligand), which facilitates AhR translocation to the nucleus and
Exogenous and endogenous ligands critically shape AhR function
Dioxin is widely used as a surrogate ligand for AhR but its use is problematic in revealing the true function of AhR because it is not quickly metabolized in the body (its half-life is ∼2 weeks in mice and several years in adult humans 19, 20). Indeed, a proper understanding of AhR biology must differentiate between effects triggered by toxic ligands such as dioxin and physiological effects triggered by endogenous ligands. Simple extrapolation of data obtained for one ligand to all others would
Immunotoxicological evidence
In vitro and in vivo immunotoxicological studies with dioxin in relation to persistently activated AhR have revealed drastic changes in thymocyte lineage decisions, shifts in immune-cell subset frequencies, aberrant cytokine secretion and many other effects on immune functions (Figure 1). Among the most sensitive outcomes of dioxin exposure in animals is strong systemic immunosuppression of the humoral, cellular and innate immune responses. The cause–effect relationships are largely unclear and
Immune cell-specific AhR expression
Liver and lung exhibit high levels of AhR expression. However, certain hematopoietic stem cells, some dendritic cells, particular subsets of thymocytes and T-cells have similar or even higher levels of AhR expression than the liver 5, 48, 49. Immune functions and immune cells can be targeted directly or indirectly by AhR activity. Unfortunately, data on AhR protein levels are not available for many immune cell subpopulations, limiting the interpretation of causative AhR-ligand effects.
AhR and autoimmunity: a critical perspective
Except for drug-induced autoimmune reactions, most autoimmune diseases remain idiopathic. Epidemiology, anecdotal evidence and mechanistic studies have suggested links between autoimmune diseases and environmental exposure to small chemicals and/or AhR ligands or xenobiotic-metabolizing enzyme activity. For instance, links exist between dioxin and rheumatoid arthritis and between smoking and psoriasis. Other examples are given in Box 3. Autoimmunity requires the breakdown of central and/or
Conclusions and future perspectives
AhR, a sensor of small chemical compounds, is abundant in many cells of the immune system. It is involved in the metabolism of these compounds and in regulating cell differentiation, cell cycling and important homeostatic processes. Recent evidence has shown that AhR enhances Th17 differentiation and is essential for induction of IL-22. Because Th17 cells are the driving force for some autoimmune diseases, it is possible that AhR activation exacerbates (rather than induces) Th17-mediated
Acknowledgements
The research of the authors was supported by grants from Bundesministerium für Umwelt (C.E.), the Swedish Research Council for Environment, Agricultural Science and Spatial Planning (FORMAS) (A.R.), and the Medical Research Council UK and an ERC Advanced Investigator grant (G.S.).
References (73)
Dioxins: an overview
Environ. Res.
(2006)Recent advances in understanding the mechanisms of TCDD immunotoxicity
Int. Immunopharmacol.
(2002)The mammalian basic helix-loop-helix/PAS family of transcriptional regulators
Int. J. Biochem. Cell Biol.
(2004)AHR-mediated immunomodulation: the role of altered gene transcription
Biochem. Pharmacol
(2009)Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes
Toxicol. Appl. Pharmacol.
(2007)The immune system of Ahr null mutant mouse strains – not a simple mirror of xenobiotic receptor over-activation
Biochem. Pharmacol.
(2009)Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor
Biochem. Pharmacol.
(2009)- et al.
ER alpha-AHR–ARNT protein–protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription
J. Biol. Chem
(2005) Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest
J. Biol. Chem.
(2000)Ah receptor and NF-κB interplay on the stage of epigenome
Biochem. Pharmacol.
(2009)