Trends in Immunology
Volume 30, Issue 9, September 2009, Pages 447-454
Journal home page for Trends in Immunology

Review
Autoimmunity and the environment
The aryl hydrocarbon receptor in immunity

https://doi.org/10.1016/j.it.2009.06.005Get rights and content

Low-molecular-weight chemicals or xenobiotics might contribute to the increasing prevalence of allergies and autoimmunity. Certain chemicals can alter immune responses via their action on the cytosolic transcription factor aryl hydrocarbon receptor (AhR). AhR recognizes numerous small xenobiotic and natural molecules, such as dioxin and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Although AhR is best known for mediating dioxin toxicity, knockout studies have indicated that AhR also plays a role in normal physiology, including certain immune responses. In particular, Th17 cells and dendritic cells express high levels of AhR. We review here current evidence for the physiological role of AhR in the immune system, focussing in particular on T-cell biology.

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)

  • A. Puga

    The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways

    Biochem. Pharmacol.

    (2009)
  • M. Frericks

    Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response

    Toxicol. Appl. Pharmacol

    (2008)
  • R. Miniero

    An overview of TCDD half-life in mammals and its correlation to body weight

    Chemosphere

    (2001)
  • M.K. Bunger

    Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor

    J. Biol. Chem.

    (2003)
  • A. Rannug

    Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances

    J. Biol. Chem.

    (1987)
  • Y.D. Wei

    Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole

    Chem. Biol. Interact

    (1998)
  • U. Rannug

    Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands

    Chem. Biol.

    (1995)
  • E. Wincent

    The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans

    J. Biol. Chem

    (2009)
  • L. Bergander

    Metabolic fate of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole

    Chem. Biol. Interact

    (2004)
  • S.K. Katiyar

    Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1

    J. Invest. Dermatol.

    (2000)
  • F. Matsumura

    Biological functions of the arylhydrocarbon receptor: beyond induction of cytochrome P450 s. Introduction to this special issue

    Biochem. Pharmacol

    (2009)
  • F.X. van Leeuwen

    Dioxins: WHO's tolerable daily intake (TDI) revisited

    Chemosphere

    (2000)
  • K.P. Singh

    The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations

    Biochem. Pharmacol.

    (2009)
  • Y. Hirabayashi et al.

    Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells

    Biochem. Pharmacol.

    (2009)
  • E. Hauben

    Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells

    Blood

    (2008)
  • B.P. Lawrence

    Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

    Blood

    (2008)
  • L.A. Zenewicz

    Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation

    Immunity

    (2007)
  • K. Wolk

    IL-22 increases the innate immunity of tissues

    Immunity

    (2004)
  • D. Richter-Hintz

    Allelic variants of drug metabolizing enzymes as risk factors in psoriasis

    J. Invest. Dermatol.

    (2003)
  • L. Klareskog

    Rheumatoid arthritis

    Lancet

    (2009)
  • D. D’Cruz

    Autoimmune diseases associated with drugs, chemicals and environmental factors

    Toxicol. Lett.

    (2000)
  • L. Naldi

    Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study

    J. Invest. Dermatol.

    (2005)
  • Y.V. Sun

    Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences

    Nucleic Acids Res.

    (2004)
  • T.V. Beischlag

    The aryl hydrocarbon receptor complex and the control of gene expression

    Crit Rev. Eukaryot. Gene Expr.

    (2008)
  • J.L. Marlowe

    The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis

    Mol. Biol. Cell

    (2008)
  • F. Ohtake

    Dioxin receptor is a ligand-dependent E3 ubiquitin ligase

    Nature

    (2007)
  • Cited by (372)

    • Polycyclic aromatic hydrocarbons (PAHs) may explain the paradoxical effects of cigarette use on preeclampsia (PE)

      2022, Toxicology
      Citation Excerpt :

      AhR activity affects syncytiotrophoblast immunity and the endothelium of large blood vessels in the villi and umbilical cord (Li et al., 2020). AhR is a central regulator of immune function and differentiation (Esser et al., 2009), which may have implications as there are numerous immunologic and inflammatory adaptations occurring during pregnancy (St-Germain et al., 2020). Thus, we hypothesize that exposure to PAHs via cigarette smoke may impair a potential role for endogenous AhR ligands for proper placental development and function.

    View all citing articles on Scopus
    View full text