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The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation

Nature Reviews Drug Discovery volume 24, pages 610–630 (2025)Cite this article

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Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.

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Fig. 1: Canonical and non-canonical AHR signalling.
Fig. 2: The AHR regulates innate and adaptative immunity.
Fig. 3: Probiotics impact AHR signalling.
Fig. 4: Nanoparticle-loaded agents for AHR modulation.

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References

  1. 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). This study is the first to identify TCDD as an AHR ligand.

    Article  CAS  Google Scholar 

  2. Poland, A. & Knutson, J. C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu. Rev. Pharmacol. Toxicol. 22, 517–554 (1982).

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Gu, Y. Z., Hogenesch, J. B. & Bradfield, C. A. The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharmacol. Toxicol. 40, 519–561 (2000).

    Article  CAS  Google Scholar 

  5. Hankinson, O. The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol. 35, 307–340 (1995).

    Article  CAS  Google Scholar 

  6. Swanson, H. I. & Bradfield, C. A. The AH-receptor: genetics, structure and function. Pharmacogenetics 3, 213–230 (1993).

    Article  CAS  Google Scholar 

  7. Elferink, C. J., Ge, N. L. & Levine, A. Maximal aryl hydrocarbon receptor activity depends on an interaction with the retinoblastoma protein. Mol. Pharmacol. 59, 664–673 (2001).

    Article  CAS  Google Scholar 

  8. Shivanna, S. et al. The aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in uremia. J. Am. Soc. Nephrol. 27, 189–201 (2016).

    Article  CAS  Google Scholar 

  9. Furman, D. P., Oshchepkova, E. A., Oshchepkov, D. Y., Shamanina, M. Y. & Mordvinov, V. A. Promoters of the genes encoding the transcription factors regulating the cytokine gene expression in macrophages contain putative binding sites for aryl hydrocarbon receptor. Comput. Biol. Chem. 33, 465–468 (2009).

    Article  CAS  Google Scholar 

  10. Durrin, L. K., Jones, P. B., Fisher, J. M., Galeazzi, D. R. & Whitlock, J. P. Jr 2,3,7,8-Tetrachlorodibenzo-p-dioxin receptors regulate transcription of the cytochrome P1-450 gene. J. Cell Biochem. 35, 153–160 (1987).

    Article  CAS  Google Scholar 

  11. Mimura, J. et al. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes. Cell 2, 645–654 (1997).

    Article  CAS  Google Scholar 

  12. Vorderstrasse, B. A., Fenton, S. E., Bohn, A. A., Cundiff, J. A. & Lawrence, B. P. A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation. Toxicol. Sci. 78, 248–257 (2004).

    Article  CAS  Google Scholar 

  13. Moennikes, O. et al. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res. 64, 4707–4710 (2004).

    Article  CAS  Google Scholar 

  14. Andersson, P. et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA 99, 9990–9995 (2002).

    Article  CAS  Google Scholar 

  15. Mulero-Navarro, S. et al. Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model. J. Biol. Chem. 280, 28731–28741 (2005).

    Article  CAS  Google Scholar 

  16. Zudaire, E. et al. The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J. Clin. Invest. 118, 640–650 (2008).

    CAS  Google Scholar 

  17. Barroso, A., Mahler, J. V., Fonseca-Castro, P. H. & Quintana, F. J. The aryl hydrocarbon receptor and the gut–brain axis. Cell. Mol. Immunol. 18, 259–268 (2021).

    Article  CAS  Google Scholar 

  18. Rothhammer, V. et al. Detection of aryl hydrocarbon receptor agonists in human samples. Sci. Rep. 8, 1–8 (2018).

    Article  CAS  Google Scholar 

  19. Denison, M. S. & Faber, S. C. And now for something completely different: diversity in ligand-dependent activation of Ah receptor responses. Curr. Opin. Toxicol. 2, 124–131 (2017).

    Article  Google Scholar 

  20. Stejskalova, L., Dvorak, Z. & Pavek, P. Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr. Drug Metab. 12, 198–212 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).

    Article  CAS  Google Scholar 

  23. Bissonnette, R., Gold, L. S., Rubenstein, D. S., Tallman, A. M. & Armstrong, A. Tapinarof in the treatment of psoriasis: a review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor–modulating agent. J. Am. Acad. Dermatol. 84, 1059–1067 (2021).

    Article  CAS  Google Scholar 

  24. Larigot, L., Juricek, L., Dairou, J. & Coumoul, X. AhR signaling pathways and regulatory functions. Biochim. Open 7, 1–9 (2018).

    Article  Google Scholar 

  25. Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  Google Scholar 

  26. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008). Together with Quintana et al. (2008), this work shows that different AHR ligands trigger varying immune responses, shaping immune regulation.

    Article  CAS  Google Scholar 

  27. Dermavant Sciences. VTAMA (tapinarof) cream 1%: US prescribing information. VTAMA https://www.vtama.com/PI/ (2022).

  28. Pandini, A., Denison, M. S., Song, Y., Soshilov, A. A. & Bonati, L. Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis. Biochemistry 46, 696–708 (2007).

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. 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  Google Scholar 

  31. 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  Google Scholar 

  32. Wu, D., Potluri, N., Kim, Y. & Rastinejad, F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Mol. Cell Biol. 33, 4346–4356 (2013).

    Article  CAS  Google Scholar 

  33. Soshilov, A. & Denison, M. S. Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. J. Biol. Chem. 283, 32995–33005 (2008).

    Article  CAS  Google Scholar 

  34. Schulte, K. W., Green, E., Wilz, A., Platten, M. & Daumke, O. Structural basis for aryl hydrocarbon receptor-mediated gene activation. Structure 25, 1025–1033.e3 (2017).

    Article  CAS  Google Scholar 

  35. Reisz-Porszasz, S., Probst, M. R., Fukunaga, B. N. & Hankinson, O. Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Mol. Cell Biol. 14, 6075–6086 (1994).

    CAS  Google Scholar 

  36. Jain, S., Dolwick, K. M., Schmidt, J. V. & Bradfield, C. A. Potent transactivation domains of the Ah receptor and the Ah receptor nuclear translocator map to their carboxyl termini. J. Biol. Chem. 269, 31518–31524 (1994).

    Article  CAS  Google Scholar 

  37. Seok, S. H. et al. Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. Proc. Natl Acad. Sci. USA 114, 5431–5436 (2017).

    Article  CAS  Google Scholar 

  38. Dai, S. Q. et al. Structural insight into the ligand binding mechanism of aryl hydrocarbon receptor. Nat. Commun. 13, 6234 (2022).

    Article  CAS  Google Scholar 

  39. Wen, Z. et al. Cryo-EM structure of the cytosolic AhR complex. Structure 31, 295–308.e4 (2023).

    Article  CAS  Google Scholar 

  40. Gruszczyk, J. et al. Cryo-EM structure of the agonist-bound Hsp90–XAP2–AHR cytosolic complex. Nat. Commun. 13, 7010 (2022). Together with Dai et al. (2022) and Wen et al. (2023), this work defines structural mechanisms that regulate AHR activation.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Denis, M., Cuthill, S., Wikstrom, A. C., Poellinger, L. & Gustafsson, J. A. Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor. Biochem. Biophys. Res. Commun. 155, 801–807 (1988).

    Article  CAS  Google Scholar 

  43. Grenert, J. P. et al. The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J. Biol. Chem. 272, 23843–23850 (1997).

    Article  CAS  Google Scholar 

  44. Nair, S. C. et al. A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor. Cell Stress. Chaperones 1, 237–250 (1996).

    Article  CAS  Google Scholar 

  45. Meyer, B. K. & Perdew, G. H. Characterization of the AhR–hsp90–XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 38, 8907–8917 (1999).

    Article  CAS  Google Scholar 

  46. Carver, L. A. & Bradfield, C. A. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J. Biol. Chem. 272, 11452–11456 (1997).

    Article  CAS  Google Scholar 

  47. Dong, B. et al. FRET analysis of protein tyrosine kinase c-Src activation mediated via aryl hydrocarbon receptor. Biochim. Biophys. Acta 1810, 427–431 (2011).

    Article  CAS  Google Scholar 

  48. Antonsson, C., Whitelaw, M. L., McGuire, J., Gustafsson, J. A. & Poellinger, L. Distinct roles of the molecular chaperone hsp90 in modulating dioxin receptor function via the basic helix–loop–helix and PAS domains. Mol. Cell Biol. 15, 756–765 (1995).

    Article  CAS  Google Scholar 

  49. Kudo, I. et al. The regulation mechanisms of AhR by molecular chaperone complex. J. Biochem. 163, 223–232 (2018).

    Article  CAS  Google Scholar 

  50. 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  Google Scholar 

  51. Ramadoss, P., Petrulis, J. R., Hollingshead, B. D., Kusnadi, A. & Perdew, G. H. Divergent roles of hepatitis B virus X-associated protein 2 (XAP2) in human versus mouse Ah receptor complexes. Biochemistry 43, 700–709 (2004).

    Article  CAS  Google Scholar 

  52. Petrulis, J. R. & Perdew, G. H. The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem. Biol. Interact. 141, 25–40 (2002).

    Article  CAS  Google Scholar 

  53. Petrulis, J. R., Kusnadi, A., Ramadoss, P., Hollingshead, B. & Perdew, G. H. The hsp90 co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity. J. Biol. Chem. 278, 2677–2685 (2003).

    Article  CAS  Google Scholar 

  54. 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  Google Scholar 

  55. Pappas, B. et al. p23 protects the human aryl hydrocarbon receptor from degradation via a heat shock protein 90-independent mechanism. Biochem. Pharmacol. 152, 34–44 (2018).

    Article  CAS  Google Scholar 

  56. 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  Google Scholar 

  57. Backlund, M. & Ingelman-Sundberg, M. Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases. Cell Signal. 17, 39–48 (2005).

    Article  CAS  Google Scholar 

  58. Soshilov, A. A. & Denison, M. S. Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol. Cell Biol. 34, 1707–1719 (2014).

    Article  Google Scholar 

  59. Guyot, E., Chevallier, A., Barouki, R. & Coumoul, X. The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. Drug Discov. Today 18, 479–486 (2013).

    Article  CAS  Google Scholar 

  60. Safe, S., Jin, U. H., Park, H., Chapkin, R. S. & Jayaraman, A. Aryl hydrocarbon receptor (AHR) ligands as selective AHR modulators (SAhRMs). Int. J. Mol. Sci. https://doi.org/10.3390/ijms21186654 (2020).

  61. Giani Tagliabue, S., Faber, S. C., Motta, S., Denison, M. S. & Bonati, L. Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci. Rep. 9, 10693 (2019).

    Article  Google Scholar 

  62. Bisson, W. H. et al. Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands. J. Med. Chem. 52, 5635–5641 (2009).

    Article  CAS  Google Scholar 

  63. 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  Google Scholar 

  64. Bradfield, C. A. & Bjeldanes, L. F. Structure–activity relationships of dietary indoles: a proposed mechanism of action as modifiers of xenobiotic metabolism. J. Toxicol. Environ. Health 21, 311–323 (1987).

    Article  CAS  Google Scholar 

  65. Reyes-Hernandez, O. D. et al. 3,3′-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int. 23, 180 (2023).

    Article  CAS  Google Scholar 

  66. De Kruif, C. A. et al. Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo and enzyme induction in vitro. Chem. Biol. Interact. 80, 303–315 (1991).

    Article  Google Scholar 

  67. 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). This work describes the pro-ligand concept for AHR activation.

    Article  CAS  Google Scholar 

  68. Seok, S. H. et al. Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). J. Biol. Chem. 293, 1994–2005 (2018).

    Article  CAS  Google Scholar 

  69. Bittinger, M. A., Nguyen, L. P. & Bradfield, C. A. Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. Mol. Pharmacol. 64, 550–556 (2003).

    Article  CAS  Google Scholar 

  70. Nguyen, L. P. et al. d-Amino acid oxidase generates agonists of the aryl hydrocarbon receptor from d-tryptophan. Chem. Res. Toxicol. 22, 1897–1904 (2009).

    Article  CAS  Google Scholar 

  71. Wei, G. Z. et al. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2021091118 (2021).

  72. Nguyen, L. P. & Bradfield, C. A. The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 21, 102–116 (2008).

    Article  CAS  Google Scholar 

  73. Schmidt, J. V. & Bradfield, C. A. Ah receptor signaling pathways. Annu. Rev. Cell Dev. Biol. 12, 55–89 (1996).

    Article  CAS  Google Scholar 

  74. Ikuta, T., Eguchi, H., Tachibana, T., Yoneda, Y. & Kawajiri, K. Nuclear localization and export signals of the human aryl hydrocarbon receptor. J. Biol. Chem. 273, 2895–2904 (1998).

    Article  CAS  Google Scholar 

  75. Ikuta, T. et al. Nucleocytoplasmic shuttling of the aryl hydrocarbon receptor. J. Biochem. 127, 503–509 (2000).

    Article  CAS  Google Scholar 

  76. Ikuta, T., Kobayashi, Y. & Kawajiri, K. Phosphorylation of nuclear localization signal inhibits the ligand-dependent nuclear import of aryl hydrocarbon receptor. Biochem. Biophys. Res. Commun. 317, 545–550 (2004).

    Article  CAS  Google Scholar 

  77. Tsuji, N. et al. The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open. Bio 4, 796–803 (2014).

    Article  CAS  Google Scholar 

  78. Eguchi, H., Ikuta, T., Tachibana, T., Yoneda, Y. & Kawajiri, K. A nuclear localization signal of human aryl hydrocarbon receptor nuclear translocator/hypoxia-inducible factor 1β is a novel bipartite type recognized by the two components of nuclear pore-targeting complex. J. Biol. Chem. 272, 17640–17647 (1997).

    Article  CAS  Google Scholar 

  79. Soshilov, A. A., Motta, S., Bonati, L. & Denison, M. S. Transitional states in ligand-dependent transformation of the aryl hydrocarbon receptor into its DNA-binding form. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21072474 (2020).

  80. 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  Google Scholar 

  81. Swanson, H. I., Tullis, K. & Denison, M. S. Binding of transformed Ah receptor complex to a dioxin responsive transcriptional enhancer: evidence for two distinct heteromeric DNA-binding forms. Biochemistry 32, 12841–12849 (1993).

    Article  CAS  Google Scholar 

  82. Yao, E. F. & Denison, M. S. DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer. Biochemistry 31, 5060–5067 (1992).

    Article  CAS  Google Scholar 

  83. Sun, Y. V., Boverhof, D. R., Burgoon, L. D., Fielden, M. R. & Zacharewski, T. R. Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res. 32, 4512–4523 (2004).

    Article  CAS  Google Scholar 

  84. Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).

    Article  CAS  Google Scholar 

  85. Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

    Article  CAS  Google Scholar 

  86. Yeste, A. et al. IL-21 induces IL-22 production in CD4 + T cells. Nat. Commun. 5, 3753 (2014).

    Article  CAS  Google Scholar 

  87. Mascanfroni, I. D. et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat. Med. 21, 638–646 (2015). Together with Gandhi et al. (2010) and Yeste et al. (2014), this work uncovers the role of the AHR in T cell regulation.

    Article  CAS  Google Scholar 

  88. Nebert, D. W. & Karp, C. L. Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology. J. Biol. Chem. 283, 36061–36065 (2008).

    Article  CAS  Google Scholar 

  89. Mimura, J., Ema, M., Sogawa, K. & Fujii-Kuriyama, Y. Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes. Dev. 13, 20–25 (1999).

    Article  CAS  Google Scholar 

  90. Sakurai, S., Shimizu, T. & Ohto, U. The crystal structure of the AhRR–ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription. J. Biol. Chem. 292, 17609–17616 (2017).

    Article  CAS  Google Scholar 

  91. Ma, Q. Induction and superinduction of 2,3,7,8-tetrachlorodibenzo-rho-dioxin-inducible poly(ADP-ribose) polymerase: role of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator transcription activation domains and a labile transcription repressor. Arch. Biochem. Biophys. 404, 309–316 (2002).

    Article  CAS  Google Scholar 

  92. MacPherson, L. et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res. 41, 1604–1621 (2013).

    Article  CAS  Google Scholar 

  93. Ma, Q. & Baldwin, K. T. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. Role of the transcription activaton and DNA binding of AhR. J. Biol. Chem. 275, 8432–8438 (2000).

    Article  CAS  Google Scholar 

  94. Davarinos, N. A. & Pollenz, R. S. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. J. Biol. Chem. 274, 28708–28715 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  96. Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 (2019).

    Article  CAS  Google Scholar 

  97. Chinen, I. et al. The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis. Int. Immunol. 27, 405–415 (2015).

    Article  CAS  Google Scholar 

  98. Garcia, G. R. et al. In vivo characterization of an AHR-dependent long noncoding RNA required for proper Sox9b expression. Mol. Pharmacol. 91, 609–619 (2017).

    Article  CAS  Google Scholar 

  99. Hecht, E. et al. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation. Toxicol. Appl. Pharmacol. 280, 511–525 (2014).

    Article  CAS  Google Scholar 

  100. Nakahama, T. et al. Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc. Natl Acad. Sci. USA 110, 11964–11969 (2013).

    Article  CAS  Google Scholar 

  101. Zhang, D. D. et al. Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes. Sci. Rep. 7, 46204 (2017).

    Article  CAS  Google Scholar 

  102. Vogel, C. F. et al. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol. Endocrinol. 21, 2941–2955 (2007).

    Article  CAS  Google Scholar 

  103. Ishihara, Y., Kado, S. Y., Hoeper, C., Harel, S. & Vogel, C. F. A. Role of NF-κB RelB in aryl hydrocarbon receptor-mediated ligand specific effects. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20112652 (2019).

  104. Kim, D. W. et al. The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19, 5498–5506 (2000).

    Article  CAS  Google Scholar 

  105. Tian, Y., Ke, S., Denison, M. S., Rabson, A. B. & Gallo, M. A. Ah receptor and NF-κB interactions, a potential mechanism for dioxin toxicity. J. Biol. Chem. 274, 510–515 (1999).

    Article  CAS  Google Scholar 

  106. McBerry, C., Gonzalez, R. M., Shryock, N., Dias, A. & Aliberti, J. SOCS2-induced proteasome-dependent TRAF6 degradation: a common anti-inflammatory pathway for control of innate immune responses. PLoS ONE 7, e38384 (2012).

    Article  CAS  Google Scholar 

  107. Ovrevik, J. et al. AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells. Cell Commun. Signal. 12, 48 (2014).

    Article  Google Scholar 

  108. Salisbury, R. L. & Sulentic, C. E. The AhR and NF-κB/Rel proteins mediate the inhibitory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the 3′ immunoglobulin heavy chain regulatory region. Toxicol. Sci. 148, 443–459 (2015).

    Article  CAS  Google Scholar 

  109. Sanmarco, L. M. et al. Identification of environmental factors that promote intestinal inflammation. Nature 611, 801–809 (2022).

    Article  CAS  Google Scholar 

  110. Wilson, S. R., Joshi, A. D. & Elferink, C. J. The tumor suppressor Krüppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. J. Pharmacol. Exp. Ther. 345, 419–429 (2013).

    Article  CAS  Google Scholar 

  111. Kimura, A., Naka, T., Nohara, K., Fujii-Kuriyama, Y. & Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of TH17 cells. Proc. Natl Acad. Sci. USA 105, 9721–9726 (2008).

    Article  CAS  Google Scholar 

  112. Esteban, J. et al. Role of aryl hydrocarbon receptor (AHR) in overall retinoid metabolism: response comparisons to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure between wild-type and AHR knockout mice. Reprod. Toxicol. 101, 33–49 (2021).

    Article  CAS  Google Scholar 

  113. Widerak, M. et al. The aryl hydrocarbon receptor activates the retinoic acid receptoralpha through SMRT antagonism. Biochimie 88, 387–397 (2006).

    Article  CAS  Google Scholar 

  114. Ge, N. L. & Elferink, C. J. A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle. J. Biol. Chem. 273, 22708–22713 (1998).

    Article  CAS  Google Scholar 

  115. Puga, A. et al. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J. Biol. Chem. 275, 2943–2950 (2000).

    Article  CAS  Google Scholar 

  116. Giovannoni, F. et al. AHR is a Zika virus host factor and a candidate target for antiviral therapy. Nat. Neurosci. 23, 939–951 (2020).

    Article  CAS  Google Scholar 

  117. Ohtake, F. et al. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423, 545–550 (2003).

    Article  CAS  Google Scholar 

  118. Lee, H. G. et al. Disease-associated astrocyte epigenetic memory promotes CNS pathology. Nature https://doi.org/10.1038/s41586-024-07187-5 (2024).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  120. Luecke-Johansson, S. et al. A molecular mechanism to switch the aryl hydrocarbon receptor from a transcription factor to an E3 ubiquitin ligase. Mol. Cell Biol. https://doi.org/10.1128/MCB.00630-16 (2017).

  121. Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511, 184–190 (2014).

    Article  CAS  Google Scholar 

  122. Han, Z. et al. Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells. Cardiovasc. Res. 77, 809–818 (2008).

    Article  CAS  Google Scholar 

  123. Xiao, W., Son, J., Vorrink, S. U., Domann, F. E. & Goswami, P. C. Ligand-independent activation of aryl hydrocarbon receptor signaling in PCB3-quinone treated HaCaT human keratinocytes. Toxicol. Lett. 233, 258–266 (2015).

    Article  CAS  Google Scholar 

  124. Hahn, M. E., Karchner, S. I. & Merson, R. R. Diversity as opportunity: insights from 600 million years of AHR evolution. Curr. Opin. Toxicol. 2, 58–71 (2017).

    Article  Google Scholar 

  125. 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).

    Article  CAS  Google Scholar 

  126. Gutierrez-Vazquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).

    Article  CAS  Google Scholar 

  127. Esser, C., Rannug, A. & Stockinger, B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 30, 447–454 (2009).

    Article  CAS  Google Scholar 

  128. Cabeza-Cabrerizo, M., Cardoso, A., Minutti, C. M., Pereira da Costa, M. & Reis e Sousa, C. Dendritic cells revisited. Annu. Rev. Immunol. 39, 131–166 (2021).

    Article  CAS  Google Scholar 

  129. Quintana, F. J., Yeste, A. & Mascanfroni, I. D. Role and therapeutic value of dendritic cells in central nervous system autoimmunity. BMC Neurol. 22, 215–224 (2015).

    CAS  Google Scholar 

  130. Thordardottir, S. et al. The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells. Stem Cell Dev. 23, 955–967 (2014).

    Article  CAS  Google Scholar 

  131. Goudot, C. et al. Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity 47, 582–596.e6 (2017).

    Article  CAS  Google Scholar 

  132. Vogel, C. F. et al. Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol. Cell Biol. 91, 568–575 (2013).

    Article  CAS  Google Scholar 

  133. Platzer, B. et al. Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J. Immunol. 183, 66–74 (2009).

    Article  CAS  Google Scholar 

  134. Hwang, W. B., Kim, D. J., Oh, G. S. & Park, J. H. Aryl hydrocarbon receptor ligands indoxyl 3-sulfate and indole-3-carbinol inhibit FMS-like tyrosine kinase 3 ligand-induced bone marrow-derived plasmacytoid dendritic cell differentiation. Immune Netw. 18, e35 (2018).

    Article  Google Scholar 

  135. Ettmayer, P. et al. A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation. Am. J. Respir. Crit. Care Med. 173, 599–606 (2006).

    Article  CAS  Google Scholar 

  136. Quintana, F. J. et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 107, 20768–20773 (2010).

    Article  CAS  Google Scholar 

  137. Mascanfroni, I. D. et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14, 1054–1063 (2013).

    Article  CAS  Google Scholar 

  138. Nguyen, N. T. et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl Acad. Sci. USA 107, 19961–19966 (2010). Together with Quintana et al. (2010) and Mascanfroni et al. (2013), this work shows that AHR activation in DCs affects T cell responses.

    Article  CAS  Google Scholar 

  139. 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  Google Scholar 

  140. Chng, S. H. et al. Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity. Sci. Rep. 6, 23820 (2016).

    Article  CAS  Google Scholar 

  141. Cros, A. et al. Homeostatic activation of aryl hydrocarbon receptor by dietary ligands dampens cutaneous allergic responses by controlling Langerhans cells migration. eLife https://doi.org/10.7554/eLife.86413 (2023).

  142. Cui, X. et al. Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation. Cell Biosci. 12, 46 (2022).

    Article  CAS  Google Scholar 

  143. Bankoti, J., Rase, B., Simones, T. & Shepherd, D. M. Functional and phenotypic effects of AhR activation in inflammatory dendritic cells. Toxicol. Appl. Pharmacol. 246, 18–28 (2010).

    Article  CAS  Google Scholar 

  144. Bankoti, J. et al. Effects of TCDD on the fate of naive dendritic cells. Toxicol. Sci. 115, 422–434 (2010).

    Article  CAS  Google Scholar 

  145. Hong, C. H., Lin, S. H., Clausen, B. E. & Lee, C. H. Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes TH2/Tr1 in epicutaneous protein sensitization. Proc. Natl Acad. Sci. USA 117, 12980–12990 (2020).

    Article  CAS  Google Scholar 

  146. Sadeghi Shermeh, A. et al. Differential modulation of dendritic cell biology by endogenous and exogenous aryl hydrocarbon receptor ligands. Int. J. Mol. Sci. https://doi.org/10.3390/ijms24097801 (2023).

  147. Vivier, E. The discovery of innate lymphoid cells. Nat. Rev. Immunol. 21, 616 (2021).

    Article  CAS  Google Scholar 

  148. Robinette, M. L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    Article  CAS  Google Scholar 

  149. Zhang, L. H., Shin, J. H., Haggadone, M. D. & Sunwoo, J. B. The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells. J. Exp. Med. 213, 2249–2257 (2016).

    Article  CAS  Google Scholar 

  150. Curio, S. & Belz, G. T. The unique role of innate lymphoid cells in cancer and the hepatic microenvironment. Cell Mol. Immunol. 19, 1012–1029 (2022).

    Article  CAS  Google Scholar 

  151. Mjosberg, J. M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12, 1055–1062 (2011).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  153. 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).

    Article  Google Scholar 

  154. Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).

    Article  CAS  Google Scholar 

  155. Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  157. Li, S., Bostick, J. W. & Zhou, L. Regulation of innate lymphoid cells by aryl hydrocarbon receptor. Front. Immunol. 8, 1909 (2017).

    Article  Google Scholar 

  158. Schnell, A., Littman, D. R. & Kuchroo, V. K. TH17 cell heterogeneity and its role in tissue inflammation. Nat. Immunol. 24, 19–29 (2023).

    Article  CAS  Google Scholar 

  159. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    Article  CAS  Google Scholar 

  160. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  161. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    Article  CAS  Google Scholar 

  162. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

  163. Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991–999 (2012).

    Article  CAS  Google Scholar 

  164. McGeachy, M. J. GM-CSF: the secret weapon in the TH17 arsenal. Nat. Immunol. 12, 521–522 (2011).

    Article  CAS  Google Scholar 

  165. Quintana, F. J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    Article  CAS  Google Scholar 

  166. Yang, X. P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12, 247–254 (2011).

    Article  CAS  Google Scholar 

  167. Veldhoen, M., Hirota, K., Christensen, J., O’Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of TH17 T cells. J. Exp. Med. 206, 43–49 (2009).

    Article  CAS  Google Scholar 

  168. Basu, R. et al. TH22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

    Article  CAS  Google Scholar 

  169. Ramirez, J. M. et al. Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur. J. Immunol. 40, 2450–2459 (2010).

    Article  CAS  Google Scholar 

  170. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nat. Immunol. 10, 864–871 (2009).

    Article  CAS  Google Scholar 

  171. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10, 857–863 (2009).

    Article  CAS  Google Scholar 

  172. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  Google Scholar 

  173. Fitzgerald, D. C. et al. Suppressive effect of IL-27 on encephalitogenic TH17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275 (2007).

    Article  CAS  Google Scholar 

  174. Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  Google Scholar 

  175. Spolski, R., Kim, H. P., Zhu, W., Levy, D. E. & Leonard, W. J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009).

    Article  CAS  Google Scholar 

  176. Takenaka, M. C., Robson, S. & Quintana, F. J. Regulation of the T cell response by CD39. Trends Immunol. 37, 427–439 (2016).

    Article  CAS  Google Scholar 

  177. Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).

    Article  CAS  Google Scholar 

  178. 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  Google Scholar 

  179. Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).

    Article  CAS  Google Scholar 

  180. Liu, Y. et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 22, 358–369 (2021).

    Article  CAS  Google Scholar 

  181. 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  Google Scholar 

  182. Winans, B. et al. Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. J. Immunol. 194, 4446–4457 (2015).

    Article  CAS  Google Scholar 

  183. Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26, 261–292 (2008).

    Article  CAS  Google Scholar 

  184. Vaidyanathan, B. et al. The aryl hydrocarbon receptor controls cell-fate decisions in B cells. J. Exp. Med. 214, 197–208 (2017).

    Article  CAS  Google Scholar 

  185. Piper, C. J. M. et al. Aryl hydrocarbon receptor contributes to the transcriptional program of IL-10-producing regulatory B cells. Cell Rep. 29, 1878–1892.e7 (2019).

    Article  CAS  Google Scholar 

  186. McGovern, K. et al. Discovery and characterization of a novel aryl hydrocarbon receptor inhibitor, IK-175, and its inhibitory activity on tumor immune suppression. Mol. Cancer Ther. 21, 1261–1272 (2022).

    Article  CAS  Google Scholar 

  187. Perdew, G. H. et al. The Ah receptor from toxicity to therapeutics: report from the 5th AHR Meeting at Penn State University, USA, June 2022. Int. J. Mol. Sci. https://doi.org/10.3390/ijms24065550 (2023).

  188. Di Meglio, P. et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 40, 989–1001 (2014). This work highlights the crucial role of the AHR in inflammatory skin diseases.

    Article  Google Scholar 

  189. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article  Google Scholar 

  190. Tsuji, G. et al. Difamilast, a topical phosphodiesterase 4 inhibitor, produces soluble ST2 via the AHR–NRF2 axis in human keratinocytes. Int. J. Mol. Sci. https://doi.org/10.3390/ijms25147910 (2024).

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

    Article  CAS  Google Scholar 

  192. Bissonnette, R., Saint-Cyr Proulx, E., Jack, C. & Maari, C. Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research. J. Eur. Acad. Dermatol. Venereol. 37, 1168–1174 (2023).

    Article  CAS  Google Scholar 

  193. Bissonnette, R. et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial. J. Eur. Acad. Dermatol. Venereol. 26, 1516–1521 (2012).

    Article  CAS  Google Scholar 

  194. Bissonnette, R. et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2A, randomized, placebo-controlled clinical trial. Arch. Dermatol. 146, 446–449 (2010).

    Article  CAS  Google Scholar 

  195. Bissonnette, R. et al. Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial. Br. J. Dermatol. 166, 853–860 (2012).

    Article  CAS  Google Scholar 

  196. Peppers, J. et al. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 80, 89–98.e3 (2019).

    Article  CAS  Google Scholar 

  197. Robbins, K. et al. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J. Am. Acad. Dermatol. 80, 714–721 (2019).

    Article  CAS  Google Scholar 

  198. Sutter, C. H. et al. Ligand activation of the aryl hydrocarbon receptor upregulates epidermal uridine diphosphate glucose ceramide glucosyltransferase and glucosylceramides. J. Invest. Dermatol. 143, 1964–1972.e4 (2023).

    Article  CAS  Google Scholar 

  199. Koch, M. et al. Quantitative proteomics identifies reduced NRF2 activity and mitochondrial dysfunction in atopic dermatitis. J. Invest. Dermatol. 143, 220–231.e7 (2023).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  201. 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  Google Scholar 

  202. Mooney, N. et al. Tapinarof inhibits the formation, cytokine production, and persistence of resident memeory T-cells in vitro. J. Investig. Dermatol. 142, B26 (2022).

    Article  Google Scholar 

  203. Jett, J. E. et al. Tapinarof cream 1% for extensive plaque psoriasis: a maximal use trial on safety, tolerability, and pharmacokinetics. Am. J. Clin. Dermatol. 23, 83–91 (2022).

    Article  Google Scholar 

  204. Igarashi, A., Tsuji, G., Fukasawa, S., Murata, R. & Yamane, S. Tapinarof cream for the treatment of plaque psoriasis: efficacy and safety results from 2 Japanese phase 3 trials. J. Dermatol. https://doi.org/10.1111/1346-8138.17423 (2024).

    Article  Google Scholar 

  205. Silverberg, J. I. et al. in 32nd European Academy of Dermatology and Venereology Congress (Medicom, 2023).

  206. Silverberg, J. I., Boguniewicz, M., Rubenstein, D., Tallman, A. & Brown, P. Tapinarof cream improved itch on two phase 3 trials of moderate to severe artopic dermatitis. Ann. Allergy Asthma Immunol. 131, P282 (2023).

    Article  Google Scholar 

  207. Rodríguez Murúa, S., Farez, M. F. & Quintana, F. J. The immune response in multiple sclerosis. Annu. Rev. Pathol. Mech. Dis. 17, 121–139 (2022).

    Article  Google Scholar 

  208. Rothhammer, V. et al. Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS. Neurol. Neuroimmunol. Neuroinflamm. 4, e359 (2017).

    Article  Google Scholar 

  209. Rouse, M., Singh, N. P., Nagarkatti, P. S. & Nagarkatti, M. Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and TH17 cells. Br. J. Pharmacol. 169, 1305–1321 (2013).

    Article  CAS  Google Scholar 

  210. Charabati, M., Wheeler, M. A., Weiner, H. L. & Quintana, F. J. Multiple sclerosis: neuroimmune crosstalk and therapeutic targeting. Cell 186, 1309–1327 (2023).

    Article  CAS  Google Scholar 

  211. Dossi, E., Vasile, F. & Rouach, N. Human astrocytes in the diseased brain. Brain Res. Bull. 136, 139–156 (2018).

    Article  CAS  Google Scholar 

  212. Wheeler, M. A. & Quintana, F. J. Regulation of astrocyte functions in multiple sclerosis. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a029009 (2019).

  213. Colonna, M. & Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 (2017).

    Article  CAS  Google Scholar 

  214. Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).

    Article  CAS  Google Scholar 

  215. 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  Google Scholar 

  216. Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018). Together with Rothhammer et al. (2016), this work identifies the AHR in astrocytes and microglia as a regulator of CNS inflammation.

    Article  CAS  Google Scholar 

  217. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).

    Article  CAS  Google Scholar 

  218. Law, C. et al. Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus. Nature 631, 857–866 (2024). This work shows that the AHR is a negative regulator of the pathogenic immune response in SLE.

    Article  CAS  Google Scholar 

  219. Shinde, R. et al. Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 19, 571–582 (2018).

    Article  CAS  Google Scholar 

  220. Mohammadi, S., Memarian, A., Sedighi, S., Behnampour, N. & Yazdani, Y. Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: a crucial role for aryl hydrocarbon receptor. Autoimmunity 51, 199–209 (2018).

    Article  CAS  Google Scholar 

  221. Yu, H. et al. Association between the ratio of aryl hydrocarbon receptor (AhR) in TH17 cells to AhR in Treg cells and SLE skin lesions. Int. Immunopharmacol. 69, 257–262 (2019).

    Article  CAS  Google Scholar 

  222. Pernomian, L., Duarte-Silva, M. & de Barros Cardoso, C. R. The aryl hydrocarbon receptor (AHR) as a potential target for the control of intestinal inflammation: insights from an immune and bacteria sensor receptor. Clin. Rev. Allergy Immunol. 59, 382–390 (2020).

    Article  CAS  Google Scholar 

  223. Schiering, C., Vonk, A., Das, S., Stockinger, B. & Wincent, E. Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem. Pharmacol. 151, 47–58 (2018).

    Article  CAS  Google Scholar 

  224. Keir, M., Yi, Y., Lu, T. & Ghilardi, N. The role of IL-22 in intestinal health and disease. J. Exp. Med. 217, e20192195 (2020).

    Article  Google Scholar 

  225. Gronke, K. et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566, 249–253 (2019).

    Article  CAS  Google Scholar 

  226. Furumatsu, K. et al. A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig. Dis. Sci. 56, 2532–2544 (2011).

    Article  CAS  Google Scholar 

  227. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016). This study describes how IBD-linked mutations in CARD9 diminish the abundance of AHR agonist-producing members of the intestinal microbiome.

    Article  CAS  Google Scholar 

  228. Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248, 248.e1 (2011).

    Article  CAS  Google Scholar 

  229. 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  Google Scholar 

  230. Goettel, J. A. et al. AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep. 17, 1318–1329 (2016).

    Article  CAS  Google Scholar 

  231. Uchiyama, K. et al. Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: an investigator-initiated multicenter double-blind clinical trial. PLoS ONE 15, e0241337 (2020).

    Article  CAS  Google Scholar 

  232. Casaro, M., Souza, V. R., Oliveira, F. A. & Ferreira, C. M. OVA-induced allergic airway inflammation mouse model. Methods Mol. Biol. 1916, 297–301 (2019).

    Article  CAS  Google Scholar 

  233. Traboulsi, H. et al. Differential regulation of the asthmatic phenotype by the aryl hydrocarbon receptor. Front. Physiol. 12, 720196 (2021).

    Article  Google Scholar 

  234. Xu, T. et al. Aryl hydrocarbon receptor protects lungs from cockroach allergen-induced inflammation by modulating mesenchymal stem cells. J. Immunol. 195, 5539–5550 (2015).

    Article  CAS  Google Scholar 

  235. Caminati, M., Vaia, R., Furci, F., Guarnieri, G. & Senna, G. Uncontrolled asthma: unmet needs in the management of patients. J. Asthma Allergy 14, 457–466 (2021).

    Article  Google Scholar 

  236. Fadadu, R. P. et al. Association of wildfire air pollution with clinic visits for psoriasis. JAMA Netw. Open 6, e2251553 (2023).

    Article  Google Scholar 

  237. Fadadu, R. P. et al. Association of exposure to wildfire air pollution with exacerbations of atopic dermatitis and itch among older adults. JAMA Netw. Open. 5, e2238594 (2022).

    Article  Google Scholar 

  238. Fadadu, R. P. et al. Association of wildfire air pollution and health care use for atopic dermatitis and itch. JAMA Dermatol. 157, 658–666 (2021).

    Article  Google Scholar 

  239. Kim, B. E. et al. Particulate matter causes skin barrier dysfunction. JCI Insight https://doi.org/10.1172/jci.insight.145185 (2021).

  240. Wong, T. H. et al. A prominent air pollutant, indeno[1,2,3-cd]pyrene, enhances allergic lung inflammation via aryl hydrocarbon receptor. Sci. Rep. 8, 5198 (2018).

    Article  Google Scholar 

  241. Chiba, T., Chihara, J. & Furue, M. Role of the arylhydrocarbon receptor (AhR) in the pathology of asthma and COPD. J. Allergy 2012, 372384 (2012).

    Article  Google Scholar 

  242. Jasper, A. E., McIver, W. J., Sapey, E. & Walton, G. M. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res https://doi.org/10.12688/f1000research.18411.1 (2019).

  243. Loughman, J. A., Yarbrough, M. L., Tiemann, K. M. & Hunstad, D. A. Local generation of kynurenines mediates inhibition of neutrophil chemotaxis by uropathogenic Escherichia coli. Infect. Immun. 84, 1176–1183 (2016).

    Article  CAS  Google Scholar 

  244. Nganou-Makamdop, K. et al. Type I IFN signaling blockade by a PASylated antagonist during chronic SIV infection suppresses specific inflammatory pathways but does not alter T cell activation or virus replication. PLoS Pathog. 14, e1007246 (2018).

    Article  Google Scholar 

  245. Yamada, T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. Nat. Immunol. 17, 687–694 (2016). This work identifies the AHR as a negative regulator of type I interferon responses against viruses.

    Article  CAS  Google Scholar 

  246. Giovannoni, F. et al. AHR signaling is induced by infection with coronaviruses. Nat. Commun. 12, 5148 (2021).

    Article  CAS  Google Scholar 

  247. Silginer, M. et al. The aryl hydrocarbon receptor links integrin signaling to the TGF-β pathway. Oncogene 35, 3260–3271 (2016).

    Article  CAS  Google Scholar 

  248. Yang, X. et al. Constitutive regulation of CYP1B1 by the aryl hydrocarbon receptor (AhR) in pre-malignant and malignant mammary tissue. J. Cell Biochem. 104, 402–417 (2008).

    Article  CAS  Google Scholar 

  249. Stanford, E. A. et al. Role for the aryl hydrocarbon receptor and diverse ligands in oral squamous cell carcinoma migration and tumorigenesis. Mol. Cancer Res. 14, 696–706 (2016).

    Article  CAS  Google Scholar 

  250. Stanford, E. A. et al. The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. BMC Biol. 14, 20 (2016).

    Article  Google Scholar 

  251. Jin, U. H., Kim, S. B. & Safe, S. Omeprazole inhibits pancreatic cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem. Res. Toxicol. 28, 907–918 (2015).

    Article  CAS  Google Scholar 

  252. Wang, K. et al. An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells. Cancer Lett. 340, 63–71 (2013).

    Article  CAS  Google Scholar 

  253. Chen, J. Y. et al. Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Res. 16, 410 (2014).

    Article  Google Scholar 

  254. D’Amato, N. C. et al. A TDO2–AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 75, 4651–4664 (2015).

    Article  Google Scholar 

  255. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011). This work shows that cancer cells produce AHR agonists to boost tumour growth.

    Article  CAS  Google Scholar 

  256. Liu, Y. et al. Blockade of IDO–kynurenine–AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells. Nat. Commun. 8, 15207 (2017).

    Article  Google Scholar 

  257. Kenison, J. E. et al. The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation. Proc. Natl. Acad. Sci. USA https://doi.org/10.1073/pnas.2012692118 (2021).

  258. Sadik, A. et al. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell 182, 1252–1270.e34 (2020).

    Article  CAS  Google Scholar 

  259. Balachandran, V. P. et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17, 1094–1100 (2011).

    Article  CAS  Google Scholar 

  260. Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005).

    Article  CAS  Google Scholar 

  261. Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 2497–2502 (2012).

    Article  CAS  Google Scholar 

  262. Hezaveh, K. et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55, 324–340.e8 (2022).

    Article  CAS  Google Scholar 

  263. Fong, W. et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut 72, 2272–2285 (2023).

    Article  CAS  Google Scholar 

  264. St Paul, M. et al. IL6 induces an IL22+CD8+ T-cell subset with potent antitumor function. Cancer Immunol. Res. 8, 321–333 (2020).

    Article  CAS  Google Scholar 

  265. Bender, M. J. et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell 186, 1846–1862.e26 (2023).

    Article  CAS  Google Scholar 

  266. Sugatani, J. et al. Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet. Nutr. Metab. 9, 23 (2012).

    Article  CAS  Google Scholar 

  267. Adachi, J. et al. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J. Biol. Chem. 276, 31475–31478 (2001).

    Article  CAS  Google Scholar 

  268. Chauvigne-Hines, L. M., Clarke, C. A., Gernert, D. L., Green, S. J. & Watson, B. M. AHR agonists. US Patent 2023/0159493 (2023).

  269. Carson, C. A., Clarke, C. A., Gernert, D. L., Holloway, W. G. & Barrett, D. G. AHR agonists. US Patent 2023/0127797 (2023).

  270. Kaye, J. et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 113, E6145–E6152 (2016).

    Article  CAS  Google Scholar 

  271. Comi, G. et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N. Engl. J. Med. 366, 1000–1009 (2012).

    Article  CAS  Google Scholar 

  272. Vollmer, T. L. et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J. Neurol. 261, 773–783 (2014).

    Article  CAS  Google Scholar 

  273. Garhöfer, G. et al. in International Ocular Inflammation Society (IOIS) Meeting (ed. van de Kerkhof, P.) (Medicom, 2023).

  274. Rothhammer, V. et al. Aryl hydrocarbon receptor activation in astrocytes by laquinimod ameliorates autoimmune inflammation in the CNS. Neurol. Neuroimmunol. Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000946 (2021).

  275. Sanders, M. E., Merenstein, D. J., Reid, G., Gibson, G. R. & Rastall, R. A. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat. Rev. Gastroenterol. Hepatol. 16, 605–616 (2019).

    Article  Google Scholar 

  276. Khalesi, S. et al. A review of probiotic supplementation in healthy adults: helpful or hype? Eur. J. Clin. Nutr. 73, 24–37 (2019).

    Article  CAS  Google Scholar 

  277. Suez, J., Zmora, N., Segal, E. & Elinav, E. The pros, cons, and many unknowns of probiotics. Nat. Med. 25, 716–729 (2019).

    Article  CAS  Google Scholar 

  278. Canale, F. P. et al. Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature 598, 662–666 (2021).

    Article  CAS  Google Scholar 

  279. Sanmarco, L. M. et al. Lactate limits CNS autoimmunity by stabilizing HIF-1ɑ in dendritic cells. Nature 620, 881–889 (2023).

    Article  CAS  Google Scholar 

  280. Scott, B. M. et al. Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease. Nat. Rev. Genet. 27, 1212–1222 (2021).

    Article  CAS  Google Scholar 

  281. 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  Google Scholar 

  282. 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  Google Scholar 

  283. Xia, Y. et al. Lactobacillus-derived indole-3-lactic acid ameliorates colitis in cesarean-born offspring via activation of aryl hydrocarbon receptor. iScience 26, 108279 (2023).

    Article  CAS  Google Scholar 

  284. Gu, Z. et al. Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis. Food Funct. 12, 10184–10195 (2021).

    Article  CAS  Google Scholar 

  285. Cui, Q. Y. et al. Bifidobacterium bifidum relieved DSS-induced colitis in mice potentially by activating the aryl hydrocarbon receptor. Food Funct. 13, 5115–5123 (2022).

    Article  CAS  Google Scholar 

  286. Cui, Q. et al. Bifidobacterium bifidum ameliorates DSS-induced colitis in mice by regulating AHR/NRF2/NLRP3 inflammasome pathways through indole-3-lactic acid production. J. Agric. Food Chem. 71, 1970–1981 (2023).

    Article  CAS  Google Scholar 

  287. Fei, Y. et al. The role of dihydroresveratrol in enhancing the synergistic effect of Ligilactobacillus salivarius Li01 and resveratrol in ameliorating colitis in mice. Research 2022, 9863845 (2022).

    Article  CAS  Google Scholar 

  288. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).

    Article  Google Scholar 

  289. Hou, K. et al. Microbiota in health and diseases. Signal. Transduct. Target. Ther. 7, 135 (2022).

    Article  Google Scholar 

  290. 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  Google Scholar 

  291. Rankin, L. C. et al. Dietary tryptophan deficiency promotes gut RORγt+ Treg cells at the expense of Gata3+ Treg cells and alters commensal microbiota metabolism. Cell Rep. 42, 112135 (2023).

    Article  CAS  Google Scholar 

  292. Hou, Q. et al. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ. 25, 1657–1670 (2018).

    Article  CAS  Google Scholar 

  293. Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8ɑ ɑ+ T cells. Science 357, 806–810 (2017).

    Article  CAS  Google Scholar 

  294. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  CAS  Google Scholar 

  295. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 9, 615–627 (2010).

    Article  CAS  Google Scholar 

  296. Chen, Y. et al. Colon-targeted delivery of indole acetic acid helps regulate gut motility by activating the AHR signaling pathway. Nutrients https://doi.org/10.3390/nu15194282 (2023).

  297. Zhu, M. Z. et al. Edible exosome-like nanoparticles from Portulaca oleracea L mitigate DSS-induced colitis via facilitating double-positive CD4+CD8+ T cells expansion. J. Nanobiotechnol. 21, 309 (2023).

    Article  CAS  Google Scholar 

  298. Yeste, A., Nadeau, M., Burns, E. J., Weiner, H. L. & Quintana, F. J. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 11270–11275 (2012).

    Article  CAS  Google Scholar 

  299. Yeste, A. et al. Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2. Sci. Signal. 9, ra61 (2016).

    Article  Google Scholar 

  300. Kenison, J. E. et al. Tolerogenic nanoparticles suppress central nervous system inflammation. Proc. Natl Acad. Sci. USA 117, 32017–32028 (2020).

    Article  CAS  Google Scholar 

  301. Zdioruk, M. et al. PPRX-1701, a nanoparticle formulation of 6′-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models. Cell Rep. Med. 4, 101019 (2023).

    Article  CAS  Google Scholar 

  302. Quintana, F. J. & Sherr, D. H. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol. Rev. 65, 1148–1161 (2013).

    Article  CAS  Google Scholar 

  303. Dolciami, D. et al. Targeting aryl hydrocarbon receptor for next-generation immunotherapies: selective modulators (SAhRMs) versus rapidly metabolized ligands (RMAhRLs). Eur. J. Med. Chem. 185, 111842 (2020).

    Article  CAS  Google Scholar 

  304. Hitch, T. C. A. et al. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunol. 15, 1095–1113 (2022).

    Article  CAS  Google Scholar 

  305. Paris, A. et al. The AhR–SRC axis as a therapeutic vulnerability in BRAFi-resistant melanoma. EMBO Mol. Med. 14, e15677 (2022).

    Article  CAS  Google Scholar 

  306. DiNatale, B. C., Schroeder, J. C. & Perdew, G. H. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol. Carcinog. 50, 173–183 (2011).

    Article  CAS  Google Scholar 

  307. Litzenburger, U. M. et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget 5, 1038–1051 (2014).

    Article  Google Scholar 

  308. Novikov, O. et al. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER-/PR-/Her2- human breast cancer cells. Mol. Pharmacol. 90, 674–688 (2016).

    Article  CAS  Google Scholar 

  309. Esser, C. et al. Old receptor, new tricks-the ever-expanding universe of aryl hydrocarbon receptor functions. Report from the 4th AHR Meeting, 29–31 August 2018 in Paris, France. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19113603 (2018).

  310. Riemschneider, S. et al. Aryl hydrocarbon receptor activation by benzo(a)pyrene inhibits proliferation of myeloid precursor cells and alters the differentiation state as well as the functional phenotype of murine bone marrow-derived macrophages. Toxicol. Lett. 296, 106–113 (2018).

    Article  CAS  Google Scholar 

  311. Hwang, J. A., Lee, J. A., Cheong, S. W., Youn, H. J. & Park, J. H. Benzo(a)pyrene inhibits growth and functional differentiation of mouse bone marrow-derived dendritic cells. Downregulation of RelB and eIF3 p170 by benzo(a)pyrene. Toxicol. Lett. 169, 82–90 (2007).

    Article  CAS  Google Scholar 

  312. Lee, J. A. et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates functional differentiation of mouse bone marrow-derived dendritic cells. Downregulation of RelB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Lett. 173, 31–40 (2007).

    Article  CAS  Google Scholar 

  313. Crunkhorn, S. Autoimmune disease: aryl hydrocarbon receptor suppresses inflammation. Nat. Rev. Drug Discov. 17, 470 (2018).

    Google Scholar 

  314. Sameir, M. et al. The increased frequency of type 1 regulatory T (Tr1) cells and the altered expression of aryl hydrocarbon receptor (AHR) and interferon regulatory factor-4 (IRF4) genes in type 1 diabetes: a case–control study. Cureus 16, e65749 (2024).

    Google Scholar 

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Acknowledgements

The authors thank all other Quintana laboratory members for helpful discussion related to this study. This work was supported by grants NS102807, ES02530, ES029136, AI126880 from the National Institutes of Health (NIH); RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society (NMSS); RSG-14-198-01-LIB from the American Cancer Society; and PA-1604-08459 from the International Progressive MS Alliance. C.M.P. is supported by NMSS (FG-2307-42209) and Mayer Foundation.

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Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Carolina M. Polonio & Francisco J. Quintana

  2. Dermavant Sciences Inc., Morrisville, NC, USA

    Kimberly A. McHale & David Rubenstein

  3. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA

    David H. Sherr

  4. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Francisco J. Quintana

  5. Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Francisco J. Quintana

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  1. Carolina M. Polonio
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  5. Francisco J. Quintana
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Correspondence to Francisco J. Quintana.

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Competing interests

K.A.M. and D.R. are employees of Dermavant Sciences, for which they receive financial compensation in the form of salary and stock options. D.H.S. holds equity in and is a co-founder of Hercules Pharmaceuticals. F.J.Q is the Scientific Founder of AnTolRx and Violet Therapeutics, companies developing novel therapies for inflammatory and neurologic disorders; and is a consultant for Dermavant Sciences. C.M.P. declares no competing interests.

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Polonio, C.M., McHale, K.A., Sherr, D.H. et al. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nat Rev Drug Discov 24, 610–630 (2025). https://doi.org/10.1038/s41573-025-01172-x

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