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The role of the AHR in host–pathogen interactions

Nature Reviews Immunology (2024)Cite this article

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Abstract

Host–microorganism encounters take place in many different ways and with different types of outcomes. Three major types of microorganisms need to be distinguished: (1) pathogens that cause harm to the host and must be controlled; (2) environmental microorganisms that can be ignored but must be controlled at higher abundance; and (3) symbiotic microbiota that require support by the host. Recent evidence indicates that the aryl hydrocarbon receptor (AHR) senses and initiates signalling and gene expression in response to a plethora of microorganisms and infectious conditions. It was originally identified as a receptor that binds xenobiotics. However, it was subsequently found to have a critical role in numerous biological processes, including immunity and inflammation and was recently classified as a pattern recognition receptor. Here we review the role of the AHR in host–pathogen interactions, focusing on AHR sensing of different microbial classes, the ligands involved, responses elicited and disease outcomes. Moreover, we explore the therapeutic potential of targeting the AHR in the context of infection.

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Fig. 1: Schematic representation of the AHR domains and orthologues.
Fig. 2: Schematic representation of the AHR signalling pathways.
Fig. 3: Bacteria and the AHR.
Fig. 4: AHR involvement in Pseudomonas aeruginosa quorum-sensing.
Fig. 5: Fungi, parasites and viruses and the AHR.

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References

  1. Kewley, R. J., Whitelaw, M. L. & Chapman-Smith, A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int. J. Biochem. Cell Biol. 36, 189–204 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Greenlee, W. F. & Poland, A. Nuclear uptake of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice. Role of the hepatic cytosol receptor protein. J. Biol. Chem. 254, 9814–9821 (1979).

    Article  CAS  PubMed  Google Scholar 

  3. Poland, A., Glover, E. & Kende, A. S. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251, 4936–4946 (1976).

    Article  CAS  PubMed  Google Scholar 

  4. Riddick, D. S. Fifty years of aryl hydrocarbon receptor research as reflected in the pages of Drug Metabolism and Disposition. Drug. Metab. Dispos. 51, 657–671 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Lin, L., Dai, Y. & Xia, Y. An overview of aryl hydrocarbon receptor ligands in the last two decades (2002–2022): a medicinal chemistry perspective. Eur. J. Med. Chem. 244, 114845 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Hahn, M. E. & Karchner, S. I. in The AH Receptor in Biology and Toxicology (ed. Pohjanvirta, R.) 387–403 (Wiley, 2011).

  7. Powell-Coffman, J. A., Bradfield, C. A. & Wood, W. B. Caenorhabditis elegans orthologs of the aryl hydrocarbon receptor and its heterodimerization partner the aryl hydrocarbon receptor nuclear translocator. Proc. Natl Acad. Sci. USA 95, 2844–2849 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Duncan, D. M., Burgess, E. A. & Duncan, I. Control of distal antennal identity and tarsal development in Drosophila by spineless-aristapedia, a homolog of the mammalian dioxin receptor. Genes Dev. 12, 1290–1303 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moura-Alves, P. et al. AhR sensing of bacterial pigments regulates antibacterial defence. Nature 512, 387–392 (2014). This paper shows that the AHR senses bacterial pigments and modulates the immune responses against P. aeruginosa and M. tuberculosis, proposing the AHR as a new class of PRR.

    Article  CAS  PubMed  Google Scholar 

  10. Moura-Alves, P. et al. Host monitoring of quorum sensing during Pseudomonas aeruginosa infection. Science 366, eaaw1629 (2019). This paper shows that different P. aeruginosa quorum-sensing molecules expressed at different bacterial growth stages modulate the AHR (agonists and antagonists) and AHR-elicited responses, affecting host defence against infection.

    Article  CAS  PubMed  Google Scholar 

  11. Larigot, L. et al. Identification of modulators of the C. elegans aryl hydrocarbon receptor and characterization of transcriptomic and metabolic AhR-1 profiles. Antioxidants 11, 1030 (2022). This paper shows that bacterial ligands (P. aeruginosa phenazines) activate the AHR in invertebrates (C. elegans), in opposition to dioxin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schwartzkopf, C. M. et al. Tripartite interactions between filamentous Pf4 bacteriophage, Pseudomonas aeruginosa, and bacterivorous nematodes. PLoS Pathog. 19, e1010925 (2023). This paper shows that the AHR in C. elegans (invertebrate) responds to bacterial ligands, namely, PYO from P. aeruginosa, and modulates host defence against infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fukunaga, B. N., Probst, M. R., Reisz-Porszasz, S. & Hankinson, O. Identification of functional domains of the aryl hydrocarbon receptor. J. Biol. Chem. 270, 29270–29278 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403–432 (2014). This article reviews AHR functions and molecular interactions in the immune system, focusing on barrier organs.

    Article  CAS  PubMed  Google Scholar 

  15. Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019). This article reviews the AHR transcriptional programs in the immune system and their role in autoimmune and neurological diseases.

    Article  CAS  PubMed  Google Scholar 

  16. Pongratz, I., Antonsson, C., Whitelaw, M. L. & Poellinger, L. Role of the PAS domain in regulation of dimerization and DNA binding specificity of the dioxin receptor. Mol. Cell Biol. 18, 4079–4088 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chapman-Smith, A., Lutwyche, J. K. & Whitelaw, M. L. Contribution of the Per/Arnt/Sim (PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators. J. Biol. Chem. 279, 5353–5362 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Li, D. & Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 6, 291 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Magiatis, P. et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J. Invest. Dermatol. 133, 2023–2030 (2013). This paper demonstrates that the AHR senses and is activated by yeast-derived molecules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stange, E. L. et al. Staphylococcus aureus activates the aryl hydrocarbon receptor in human keratinocytes. J. Innate Immun. 14, 582–592 (2022).

  22. Rademacher, F. et al. Staphylococcus epidermidis activates aryl hydrocarbon receptor signaling in human keratinocytes: implications for cutaneous defense. J. Innate Immun. 11, 125–135 (2019). This paper shows that S. epidermidis produces small molecules that modulate the AHR.

    Article  CAS  PubMed  Google Scholar 

  23. Engen, S. A., Rorvik, G. H., Schreurs, O., Blix, I. J. & Schenck, K. The oral commensal Streptococcus mitis activates the aryl hydrocarbon receptor in human oral epithelial cells. Int. J. Oral Sci. 9, 145–150 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takamura, T. et al. Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. Immunol. Cell Biol. 89, 817–822 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ozcam, M. et al. Gut symbionts Lactobacillus reuteri R2lc and 2010 encode a polyketide synthase cluster that activates the mammalian aryl hydrocarbon receptor. Appl. Environ. Microbiol. 85, e01661-18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dong, F. & Perdew, G. H. The aryl hydrocarbon receptor as a mediator of host–microbiota interplay. Gut Microbes 12, 1859812 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Han, H., Safe, S., Jayaraman, A. & Chapkin, R. S. Diet–host–microbiota interactions shape aryl hydrocarbon receptor ligand production to modulate intestinal homeostasis. Annu. Rev. Nutr. 41, 455–478 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Korecka, A. et al. Bidirectional communication between the aryl hydrocarbon receptor (AhR) and the microbiome tunes host metabolism. NPJ Biofilms Microbiomes 2, 16014 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  29. van den Bogaard, E. H., Esser, C. & Perdew, G. H. The aryl hydrocarbon receptor at the forefront of host–microbe interactions in the skin: a perspective on current knowledge gaps and directions for future research and therapeutic applications. Exp. Dermatol. 30, 1477–1483 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Safe, S., Cheng, Y. & Jin, U. H. The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy. Curr. Opin. Toxicol. 2, 24–29 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang, X. S., Cao, F., Zhang, Y. & Pan, H. F. Therapeutic potential of aryl hydrocarbon receptor in autoimmunity. Inflammopharmacology 28, 63–81 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Shi, J. et al. Aryl hydrocarbon receptor is a proviral host factor and a candidate pan-SARS-CoV-2 therapeutic target. Sci. Adv. 9, eadf0211 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lebwohl, M. G. et al. Phase 3 trials of tapinarof cream for plaque psoriasis. N. Engl. J. Med. 385, 2219–2229 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Strober, B. et al. One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: results from the PSOARING 3 trial. J. Am. Acad. Dermatol. 87, 800–806 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Smith, S. H. et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J. Invest. Dermatol. 137, 2110–2119 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Furue, M., Hashimoto-Hachiya, A. & Tsuji, G. Aryl hydrocarbon receptor in atopic dermatitis and psoriasis. Int. J. Mol. Sci. 20, 5424 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04200963 (2024).

  38. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04999202 (2021).

  39. Kober, C. et al. Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy. J. Immunother. Cancer 11,e007495 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. DiNatale, B. C. et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci. 115, 89–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rannug, A. et al. 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. 262, 15422–15427 (1987).

    Article  CAS  PubMed  Google Scholar 

  43. Phelan, D., Winter, G. M., Rogers, W. J., Lam, J. C. & Denison, M. S. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch. Biochem. Biophys. 357, 155–163 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Sinal, C. J. & Bend, J. R. Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. Mol. Pharmacol. 52, 590–599 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Schaldach, C. M., Riby, J. & Bjeldanes, L. F. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 38, 7594–7600 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Lamas, B., Natividad, J. M. & Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 11, 1024–1038 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Vyhlidalova, B. et al. Gut microbial catabolites of tryptophan are ligands and agonists of the aryl hydrocarbon receptor: a detailed characterization. Int. J. Mol. Sci. 21, 2614 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kurata, K. et al. Skatole regulates intestinal epithelial cellular functions through activating aryl hydrocarbon receptors and p38. Biochem. Biophys. Res. Commun. 510, 649–655 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Muku, G. E., Murray, I. A., Espin, J. C. & Perdew, G. H. Urolithin a is a dietary microbiota-derived human aryl hydrocarbon receptor antagonist. Metabolites 8, 86 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fukumoto, S. et al. Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis. Immunol. Cell Biol. 92, 460–465 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 357, 806–810 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Bansal, T., Alaniz, R. C., Wood, T. K. & Jayaraman, A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. Natl Acad. Sci. USA 107, 228–233 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Zhao, C. et al. Dietary tryptophan-mediated aryl hydrocarbon receptor activation by the gut microbiota alleviates Escherichia coli-induced endometritis in mice. Microbiol. Spectr. 10, e0081122 (2022).

    Article  PubMed  Google Scholar 

  56. O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G. & Cryan, J. F. Serotonin, tryptophan metabolism and the brain–gut–microbiome axis. Behav. Brain Res. 277, 32–48 (2015).

    Article  PubMed  Google Scholar 

  57. Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Marinelli, L. et al. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci. Rep. 9, 643 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Modoux, M. et al. Butyrate acts through HDAC inhibition to enhance aryl hydrocarbon receptor activation by gut microbiota-derived ligands. Gut Microbes 14, 2105637 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Pinto, C. J. G., Avila-Galvez, M. A., Lian, Y., Moura-Alves, P. & Nunes Dos Santos, C. Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: a strategy towards gut inflammation. Redox Biol. 61, 102622 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Beischlag, T. V., Luis Morales, J., Hollingshead, B. D. & Perdew, G. H. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr. 18, 207–250 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Garrison, P. M. et al. Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. Fundam. Appl. Toxicol. 30, 194–203 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Xu, H. et al. Generation of Tg(cyp1a:gfp) transgenic zebrafish for development of a convenient and sensitive in vivo assay for aryl hydrocarbon receptor activity. Mar. Biotechnol. 17, 831–840 (2015).

    Article  CAS  Google Scholar 

  64. Diny, N. L. et al. The aryl hydrocarbon receptor contributes to tissue adaptation of intestinal eosinophils in mice. J. Exp. Med. 219, e20210970 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Schiering, C. et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242–245 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wincent, E. et al. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 109, 4479–4484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Avilla, M. N., Malecki, K. M. C., Hahn, M. E., Wilson, R. H. & Bradfield, C. A. The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model. Chem. Res. Toxicol. 33, 860–879 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bradfield, C. A. & Bjeldanes, L. F. Dietary modification of xenobiotic metabolism — contribution of indolylic compounds present in Brassica oleracea. J. Agr. Food Chem. 35, 896–900 (1987).

    Article  CAS  Google Scholar 

  69. Bjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C. & Bradfield, C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl Acad. Sci. USA 88, 9543–9547 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Boule, L. A., Burke, C. G., Jin, G. B. & Lawrence, B. P. Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome. Sci. Rep. 8, 1826 (2018). This paper provides an example of how exposure to different AHR ligands leads to variable outcomes of FluV infection.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hinsdill, R. D., Couch, D. L. & Speirs, R. S. Immunosuppression in mice induced by dioxin (TCDD) in feed. J. Env. Pathol. Toxicol. 4, 401–425 (1980).

    CAS  Google Scholar 

  72. Luster, M. I. et al. Examination of bone marrow, immunologic parameters and host susceptibility following pre- and postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Int. J. Immunopharmacol. 2, 301–310 (1980).

    Article  CAS  PubMed  Google Scholar 

  73. Ward, E. C. et al. Immunosuppression following 7,12-dimethylbenz[a]anthracene exposure in B6C3F1 mice. I. Effects on humoral immunity and host resistance. Toxicol. Appl. Pharmacol. 75, 299–308 (1984).

    Article  CAS  PubMed  Google Scholar 

  74. Sugita-Konishi, Y., Kobayashi, K., Naito, H., Miura, K. & Suzuki, Y. Effect of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on the susceptibility to Listeria infection. Biosci. Biotechnol. Biochem. 67, 89–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Vos, J. G., Kreeftenberg, J. G., Engel, H. W., Minderhoud, A. & Van Noorle Jansen, L. M. Studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin induced immune suppression and decreased resistance to infection: endotoxin hypersensitivity, serum zinc concentrations and effect of thymosin treatment. Toxicology 9, 75–86 (1978).

    Article  CAS  PubMed  Google Scholar 

  76. Kimura, A. et al. Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production. Int. Immunol. 26, 209–220 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Zhu, R. et al. Involvement of aryl hydrocarbon receptor and aryl hydrocarbon receptor repressor in Helicobacter pylori-related gastric pathogenesis. J. Cancer 9, 2757–2764 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Huang, L., Qi, W., Zuo, Y., Alias, S. A. & Xu, W. The immune response of a warm water fish orange-spotted grouper (Epinephelus coioides) infected with a typical cold water bacterial pathogen Aeromonas salmonicida is AhR dependent. Dev. Comp. Immunol. 113, 103779 (2020).

    Article  CAS  PubMed  Google Scholar 

  79. Puyskens, A. et al. Aryl hydrocarbon receptor modulation by tuberculosis drugs impairs host defense and treatment outcomes. Cell Host Microbe 27, 238–248.e7 (2020). This paper bridges the role of the AHR in infection and therapeutic efficacy, showing that the AHR senses M. tuberculosis -derived molecules and antibiotics, modulating treatment outcomes.

    Article  CAS  PubMed  Google Scholar 

  80. Memari, B. et al. Engagement of the aryl hydrocarbon receptor in Mycobacterium tuberculosis-infected macrophages has pleiotropic effects on innate immune signaling. J. Immunol. 195, 4479–4491 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. van Soest, J. J. et al. Comparison of static immersion and intravenous injection systems for exposure of zebrafish embryos to the natural pathogen Edwardsiella tarda. BMC Immunol. 12, 58 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2011). This paper and the publication by Kiss et al. were published simultaneously showing the important role of the AHR in the immune response against C. rodentium associated with the crosstalk between the AHR, immune homeostasis and diet.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Li, S. et al. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity 49, 915–928.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mayer, M. et al. Dysregulation of stress erythropoiesis and enhanced susceptibility to Salmonella Typhimurium infection in AhR-deficient mice. J. Infect. Dis. https://doi.org/10.1093/infdis/jiae304 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Fueldner, C. et al. Aryl hydrocarbon receptor activation by benzo[a]pyrene prevents development of septic shock and fatal outcome in a mouse model of systemic Salmonella enterica infection. Cells 11, 737 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kim, S. H. et al. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol. Pharmacol. 69, 1871–1878 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Shi, L. Z. et al. The aryl hydrocarbon receptor is required for optimal resistance to Listeria monocytogenes infection in mice. J. Immunol. 179, 6952–6962 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Zhang, H. et al. Sustained AhR activity programs memory fate of early effector CD8+ T cells. Proc. Natl Acad. Sci. USA 121, e2317658121 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Dean, J. W. et al. The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function. Cell Rep. 42, 111963 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Landemaine, L. et al. Staphylococcus epidermidis isolates from atopic or healthy skin have opposite effect on skin cells: potential implication of the AHR pathway modulation. Front. Immunol. 14, 1098160 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511, 184–190 (2014). This paper shows a protective role for the AHR against infection with S. Typhimurium and S. agalactiae and in endotoxic tolerance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Vorderstrasse, B. A. & Lawrence, B. P. Protection against lethal challenge with Streptococcus pneumoniae is conferred by aryl hydrocarbon receptor activation but is not associated with an enhanced inflammatory response. Infect. Immun. 74, 5679–5686 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang, T., Wyrick, K. L., Pecka, M. R., Wills, T. B. & Vorderstrasse, B. A. Mechanistic exploration of AhR-mediated host protection against Streptococcus pneumoniae infection. Int. Immunopharmacol. 13, 490–498 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gaitanis, G. et al. AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis. J. Invest. Dermatol. 128, 1620–1625 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Gaitanis, G., Magiatis, P., Hantschke, M., Bassukas, I. D. & Velegraki, A. The Malassezia genus in skin and systemic diseases. Clin. Microbiol. Rev. 25, 106–141 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Vlachos, C., Schulte, B. M., Magiatis, P., Adema, G. J. & Gaitanis, G. Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells. Br. J. Dermatol. 167, 496–505 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, L. et al. Expression and role of aryl hydrocarbon receptor in Aspergillus fumigatus keratitis. Int. J. Ophthalmol. 13, 199–205 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zelante, T. et al. Aspergillus fumigatus tryptophan metabolic route differently affects host immunity. Cell Rep. 34, 108673 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Solis, N. V., Swidergall, M., Bruno, V. M., Gaffen, S. L. & Filler, S. G. The aryl hydrocarbon receptor governs epithelial cell invasion during oropharyngeal candidiasis. mBio 8, e00025-17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. De Luca, A. et al. IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis. PLoS Pathog. 9, e1003486 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Borghi, M. et al. Targeting the aryl hydrocarbon receptor with indole-3-aldehyde protects from vulvovaginal candidiasis via the IL-22–IL-18 cross-talk. Front. Immunol. 10, 2364 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. de Araujo, E. F., Preite, N. W., Veldhoen, M., Loures, F. V. & Calich, V. L. G. Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses. Sci. Rep. 10, 11312 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  105. de Araujo, E. F. et al. The IDO–AhR axis controls Th17/Treg immunity in a pulmonary model of fungal infection. Front. Immunol. 8, 880 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Maradana, M. R. et al. Dietary environmental factors shape the immune defense against Cryptosporidium infection. Cell Host Microbe 31, 2038–2050.e4 (2023).

    Article  CAS  PubMed  Google Scholar 

  107. Munck, N. A., Roth, J., Sunderkotter, C. & Ehrchen, J. Aryl hydrocarbon receptor-signaling regulates early Leishmania major-induced cytokine expression. Front. Immunol. 10, 2442 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Climaco-Arvizu, S. et al. Aryl hydrocarbon receptor influences nitric oxide and arginine production and alters M1/M2 macrophage polarization. Life Sci. 155, 76–84 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Elizondo, G., Rodriguez-Sosa, M., Estrada-Muniz, E., Gonzalez, F. J. & Vega, L. Deletion of the aryl hydrocarbon receptor enhances the inflammatory response to Leishmania major infection. Int. J. Biol. Sci. 7, 1220–1229 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lissner, M. M. et al. Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury. eLife 9, e60165 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Brant, F. et al. Role of the aryl hydrocarbon receptor in the immune response profile and development of pathology during Plasmodium berghei Anka infection. Infect. Immun. 82, 3127–3140 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Sanchez, Y. et al. The unexpected role for the aryl hydrocarbon receptor on susceptibility to experimental toxoplasmosis. J. Biomed. Biotechnol. 2010, 505694 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Barroso, A. et al. The aryl hydrocarbon receptor modulates production of cytokines and reactive oxygen species and development of myocarditis during Trypanosoma cruzi infection. Infect. Immun. 84, 3071–3082 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ambrosio, L. F. et al. Role of aryl hydrocarbon receptor (AhR) in the regulation of immunity and immunopathology during Trypanosoma cruzi infection. Front. Immunol. 10, 631 (2019). This paper highlights the importance of the threshold of AHR activation for the modulation of T. cruzi infection outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Poland, A., Palen, D. & Glover, E. Analysis of the four alleles of the murine aryl hydrocarbon receptor. Mol. Pharmacol. 46, 915–921 (1994).

    CAS  PubMed  Google Scholar 

  116. Ema, M. et al. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J. Biol. Chem. 269, 27337–27343 (1994).

    Article  CAS  PubMed  Google Scholar 

  117. Kashuba, E. V. et al. Regulation of transactivation function of the aryl hydrocarbon receptor by the Epstein–Barr virus-encoded EBNA-3 protein. J. Biol. Chem. 281, 1215–1223 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. House, R. V. et al. Examination of immune parameters and host resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. Toxicol. Env. Health 31, 203–215 (1990).

    Article  CAS  Google Scholar 

  119. Burleson, G. R. et al. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on influenza virus host resistance in mice. Fundam. Appl. Toxicol. 29, 40–47 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Teske, S., Bohn, A. A., Regal, J. F., Neumiller, J. J. & Lawrence, B. P. Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus. Am. J. Physiol. Lung Cell Mol. Physiol. 289, L111–L124 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Neff-LaFord, H., Teske, S., Bushnell, T. P. & Lawrence, B. P. Aryl hydrocarbon receptor activation during influenza virus infection unveils a novel pathway of IFN-γ production by phagocytic cells. J. Immunol. 179, 247–255 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Wheeler, J. L., Martin, K. C. & Lawrence, B. P. Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection. J. Immunol. 190, 659–668 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Jin, G. B., Winans, B., Martin, K. C. & Paige Lawrence, B. New insights into the role of the aryl hydrocarbon receptor in the function of CD11c+ cells during respiratory viral infection. Eur. J. Immunol. 44, 1685–1698 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jin, G. B., Moore, A. J., Head, J. L., Neumiller, J. J. & Lawrence, B. P. Aryl hydrocarbon receptor activation reduces dendritic cell function during influenza virus infection. Toxicol. Sci. 116, 514–522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lawrence, B. P., Roberts, A. D., Neumiller, J. J., Cundiff, J. A. & Woodland, D. L. Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung. J. Immunol. 177, 5819–5828 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Major, J. et al. Endothelial AHR activity prevents lung barrier disruption in viral infection. Nature 621, 813–820 (2023). This paper shows that the outcome of AHR activity upon FluV infection is tissue specific.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Giovannoni, F. et al. AHR signaling is induced by infection with coronaviruses. Nat. Commun. 12, 5148 (2021). This paper shows that infection with different coronaviruses activates the AHR as a strategy to evade immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Grunewald, M. E., Shaban, M. G., Mackin, S. R., Fehr, A. R. & Perlman, S. Murine coronavirus infection activates the aryl hydrocarbon receptor in an indoleamine 2,3-dioxygenase-independent manner, contributing to cytokine modulation and proviral TCDD-inducible-PARP expression. J. Virol. 94, e01743-19 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tang, B. S. et al. Comparative host gene transcription by microarray analysis early after infection of the Huh7 cell line by severe acute respiratory syndrome coronavirus and human coronavirus 229E. J. Virol. 79, 6180–6193 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Almeida-da-Silva, C. L. C., Matshik Dakafay, H., Liu, K. & Ojcius, D. M. Cigarette smoke stimulates SARS-CoV-2 internalization by activating AhR and increasing ACE2 expression in human gingival epithelial cells. Int. J. Mol. Sci. 22, 7669 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Tanimoto, K. et al. Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal. Sci. Rep. 11, 16629 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liu, Y. et al. Mucus production stimulated by IFN–AhR signaling triggers hypoxia of COVID-19. Cell Res. 30, 1078–1087 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Zhou, Y. H. et al. Tryptophan metabolism activates aryl hydrocarbon receptor-mediated pathway to promote HIV-1 infection and reactivation. mBio 10, e02591-19 (2019). This paper shows that the AHR binds to the HIV-1 5′ long terminal repeat to activate viral transcription and to the Tat viral protein to facilitate the recruitment of transcription factors to viral promotors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ohata, H., Tetsuka, T., Hayashi, H., Onozaki, K. & Okamoto, T. 3-Methylcholanthrene activates human immunodeficiency virus type 1 replication via aryl hydrocarbon receptor. Microbiol. Immunol. 47, 363–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Fiorito, F., Santamaria, R., Irace, C., De Martino, L. & Iovane, G. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the viral infection. Env. Res. 153, 27–34 (2017).

    Article  CAS  Google Scholar 

  136. Pokrovsky, A. G., Cherykh, A. I., Yastrebova, O. N. & Tsyrlov, I. B. 2,3,7,8-Tetrachlorodibenzo-p-dioxin as a possible activator of HIV infection. Biochem. Biophys. Res. Commun. 179, 46–51 (1991).

    Article  CAS  PubMed  Google Scholar 

  137. Gollapudi, S., Kim, C. H., Patel, A., Sindhu, R. & Gupta, S. Dioxin activates human immunodeficiency virus-1 expression in chronically infected promonocytic U1 cells by enhancing NF-κB activity and production of tumor necrosis factor-α. Biochem. Biophys. Res. Commun. 226, 889–894 (1996).

    Article  CAS  PubMed  Google Scholar 

  138. Tsyrlov, I. B. & Pokrovsky, A. Stimulatory effect of the CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin on the reproduction of HIV-1 in human lymphoid cell culture. Xenobiotica 23, 457–467 (1993).

    Article  CAS  PubMed  Google Scholar 

  139. Rao, P. S. & Kumar, S. Polycyclic aromatic hydrocarbons and cytochrome P450 in HIV pathogenesis. Front. Microbiol. 6, 550 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kueck, T., Cassella, E., Holler, J., Kim, B. & Bieniasz, P. D. The aryl hydrocarbon receptor and interferon γ generate antiviral states via transcriptional repression. eLife 7, e38867 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Chatterjee, D. et al. Identification of aryl hydrocarbon receptor as a barrier to HIV-1 infection and outgrowth in CD4+ T cells. Cell Rep. 42, 112634 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ohashi, H. et al. The aryl hydrocarbon receptor-cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly. J. Biol. Chem. 293, 19559–19571 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Giovannoni, F. et al. AHR is a Zika virus host factor and a candidate target for antiviral therapy. Nat. Neurosci. 23, 939–951 (2020). This paper presents the AHR as a potential target for therapy against ZIKV infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Vota, D. et al. Zika virus infection of first trimester trophoblast cells affects cell migration, metabolism and immune homeostasis control. J. Cell Physiol. 236, 4913–4925 (2021).

    Article  CAS  PubMed  Google Scholar 

  145. Yamada, T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. Nat. Immunol. 17, 687–694 (2016). This paper shows that AHR signalling downregulates the IFN type I response upon infection with different viruses.

    Article  CAS  PubMed  Google Scholar 

  146. Inoue, H. et al. Aryl hydrocarbon receptor-mediated induction of EBV reactivation as a risk factor for Sjogren’s syndrome. J. Immunol. 188, 4654–4662 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Jiang, Y. et al. LMP2A suppresses the role of AHR pathway through ERK signal pathway in EBV-associated gastric cancer. Virus Res. 297, 198399 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Chen, J. et al. Targeting aryl hydrocarbon receptor signaling enhances tpe I interferon-independent resistance to herpes simplex virus. Microbiol. Spectr. 9, e0047321 (2021).

    Article  PubMed  Google Scholar 

  149. Veiga-Parga, T., Suryawanshi, A. & Rouse, B. T. Controlling viral immuno-inflammatory lesions by modulating aryl hydrocarbon receptor signaling. PLoS Pathog. 7, e1002427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. McNab, F., Mayer-Barber, K., Sher, A., Wack, A. & O’Garra, A. Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Paris, A., Tardif, N., Galibert, M. D. & Corre, S. AhR and cancer: from gene profiling to targeted therapy. Int. J. Mol. Sci. 22, 752 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Safe, S., Lee, S. O. & Jin, U. H. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci. 135, 1–16 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Murray, I. A., Patterson, A. D. & Perdew, G. H. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer 14, 801–814 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hawerkamp, H. C. et al. Vemurafenib acts as an aryl hydrocarbon receptor antagonist: implications for inflammatory cutaneous adverse events. Allergy 74, 2437–2448 (2019).

    Article  CAS  PubMed  Google Scholar 

  155. Corre, S. et al. Sustained activation of the aryl hydrocarbon receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 9, 4775 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Stinn, A., Furkert, J., Kaufmann, S. H. E., Moura-Alves, P. & Kolbe, M. Novel method for quantifying AhR-ligand binding affinities using microscale thermophoresis. Biosensors 11, 60 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Cheng, Y. et al. Editor’s highlight: microbial-derived 1,4-dihydroxy-2-naphthoic acid and related compounds as aryl hydrocarbon receptor agonists/antagonists: structure–activity relationships and receptor modeling. Toxicol. Sci. 155, 458–473 (2017).

    Article  CAS  PubMed  Google Scholar 

  158. Song, J. et al. A ligand for the aryl hydrocarbon receptor isolated from lung. Proc. Natl Acad. Sci. USA 99, 14694–14699 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hubbard, T. D. et al. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lowe, M. M. et al. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS ONE 9, e87877 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Miller, C. A. 3rd. Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds. J. Biol. Chem. 272, 32824–32829 (1997).

    Article  CAS  PubMed  Google Scholar 

  162. Jin, U. H. et al. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol. 85, 777–788 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Schroeder, J. C. et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49, 393–400 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. Michaudel, C. et al. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases. Gut 72, 1296–1307 (2022).

    Article  PubMed  Google Scholar 

  165. Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

    Article  CAS  PubMed  Google Scholar 

  166. Tian, W. Z. et al. PE (0:0/14:0), an endogenous metabolite of the gut microbiota, exerts protective effects against sepsis-induced intestinal injury by modulating the AHR/CYP1A1 pathway. Clin. Sci. 137, 1753–1769 (2023).

    Article  CAS  Google Scholar 

  167. Mexia, N. et al. Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast. Arch. Biochem. Biophys. 571, 16–20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Seidel, S. D. et al. Activation of the Ah receptor signaling pathway by prostaglandins. J. Biochem. Mol. Toxicol. 15, 187–196 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Flegel, J. et al. The highly potent AhR agonist picoberin modulates Hh-dependent osteoblast differentiation. J. Med. Chem. 65, 16268–16289 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ramadoss, P. & Perdew, G. H. Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells. Mol. Pharmacol. 66, 129–136 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Chae, K., Albro, P. W., Luster, M. I. & McKinney, J. D. A screening assay for the tetrachlorodibenzo-p-dioxin receptor using the [125I]iodovaleramide derivative of trichlorodibenzo-p-dioxin as the binding ligand. Int. J. Env. Anal. Chem. 17, 267–274 (1984).

    Article  CAS  Google Scholar 

  172. Perdew, G. H. Association of the Ah receptor with the 90-kDa heat shock protein. J. Biol. Chem. 263, 13802–13805 (1988).

    Article  CAS  PubMed  Google Scholar 

  173. Meyer, B. K., Pray-Grant, M. G., Vanden Heuvel, J. P. & Perdew, G. H. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Mol. Cell Biol. 18, 978–988 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kazlauskas, A., Poellinger, L. & Pongratz, I. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor. J. Biol. Chem. 274, 13519–13524 (1999).

    Article  CAS  PubMed  Google Scholar 

  175. Enan, E. & Matsumura, F. Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochem. Pharmacol. 52, 1599–1612 (1996).

    Article  CAS  PubMed  Google Scholar 

  176. Reyes, H., Reisz-Porszasz, S. & Hankinson, O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 256, 1193–1195 (1992).

    Article  CAS  PubMed  Google Scholar 

  177. Denison, M. S., Fisher, J. M. & Whitlock, J. P. Jr. The DNA recognition site for the dioxin–Ah receptor complex. Nucleotide sequence and functional analysis. J. Biol. Chem. 263, 17221–17224 (1988).

    Article  CAS  PubMed  Google Scholar 

  178. Rijo, M. P., Diani-Moore, S., Yang, C., Zhou, P. & Rifkind, A. B. Roles of the ubiquitin ligase CUL4B and ADP-ribosyltransferase TiPARP in TCDD-induced nuclear export and proteasomal degradation of the transcription factor AHR. J. Biol. Chem. 297, 100886 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Ma, Q., Baldwin, K. T., Renzelli, A. J., McDaniel, A. & Dong, L. TCDD-inducible poly(ADP-ribose) polymerase: a novel response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem. Biophys. Res. Commun. 289, 499–506 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E. & Zhao, B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 124, 1–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wright, E. J., De Castro, K. P., Joshi, A. D. & Elferink, C. J. Canonical and non-canonical aryl hydrocarbon receptor signaling pathways. Curr. Opin. Toxicol. 2, 87–92 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Ohtake, F. et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446, 562–566 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Jia, Y. et al. Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR–c-src–c-Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis. Cell Death Dis. 10, 38 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Zhu, J. et al. Aryl hydrocarbon receptor promotes IL-10 expression in inflammatory macrophages through Src–STAT3 signaling pathway. Front. Immunol. 9, 2033 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank their colleagues in the field whose work inspired this Review. This work was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement number 951921. Y.L. was supported by the Ludwig Institute for Cancer Research Core Award.

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Authors and Affiliations

  1. IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

    Palmira Barreira-Silva & Pedro Moura-Alves

  2. i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Palmira Barreira-Silva & Pedro Moura-Alves

  3. Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

    Yilong Lian

  4. Max Planck Institute for Infection Biology, Berlin, Germany

    Stefan H. E. Kaufmann

  5. Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany

    Stefan H. E. Kaufmann

  6. Hagler Institute for Advanced Study, Texas A&M University, College Station, TX, USA

    Stefan H. E. Kaufmann

  7. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Stefan H. E. Kaufmann

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Glossary

AHR ligands

Molecules with anthropomorphic (for example, pollutants) and natural (for example, diet, host or microbiota metabolism, and microorganism derived) origin where aryl hydrocarbon receptor (AHR) binding has been confirmed.

AHR modulators

Molecules that directly or indirectly activate or inhibit the aryl hydrocarbon receptor (AHR), and where binding has not been shown.

Competitive ligand binding

Measurement of competition and displacement of radiolabelled known aryl hydrocarbon receptor (AHR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the photoaffinity ligand 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin (125IBr2N3DpD) from the AHR.

Danger-associated molecular patterns

(DAMPs). Endogenous molecules released from damaged or dying cells, such as high-mobility group box 1 and heat shock proteins, capable of eliciting an innate immune response upon recognition by a pattern recognition receptor (PRR).

Direct ligand binding

Measurement of direct ligand binding, such as microscale thermophoresis, intrinsic fluorescence quenching assays or differential scanning fluorometry, to the purified aryl hydrocarbon receptor (AHR) or AHR complex (for example, with chaperones or the AHR nuclear translocator (ARNT)).

Microorganism-associated molecular patterns

(MAMPs). Conserved microbial components such as lipids, polysaccharides and nucleic acids that are expressed/released by microorganisms, which are capable of eliciting an innate immune response upon recognition by a pattern recognition receptor (PRR).

PAS

A protein domain named after the three proteins in which it was first discovered: period circadian protein (PER), aryl hydrocarbon receptor nuclear translocator (ARNT) and single-minded protein (SIM). The PAS domain is found in bacteria and eukaryotes and acts as a molecular sensor.

Pattern recognition receptors

(PRRs). Germline-encoded receptors present in the cellular cytoplasm or membrane bound that are able to sense different molecules in health and pathological contexts, including microbial derived or components of host cells. PRRs are divided according to their localization, function, structural organization or ligand specificity.

Quorum-sensing

Process of cell–cell communication between bacteria (both intraspecies and/or interspecies) through the production and detection of molecules that induce a cell density-dependent response.

Xenobiotic

A chemical substance that is found in an organism but that is extrinsic to that organism and not naturally produced by it, including pharmaceutical drugs, pesticides, environmental pollutants and food additives, among others.

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Barreira-Silva, P., Lian, Y., Kaufmann, S.H.E. et al. The role of the AHR in host–pathogen interactions. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01088-4

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