All Issue

2025 Vol.55, Issue 4 Preview Page

Review Article

Aryl Hydrocarbon Receptor, a Critical Interface between Host Immunity and Microbiota
Abdur Rehman123
,
Young-Sang Koh123*
1Department of Microbiology and Immunology, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
2Department of Medicine, Graduate School, Jeju National University, Jeju 63243, Republic of Korea
3Jeju Research Center for Natural Medicine, Core Research Institute, Jeju National University, Jeju 63243, Republic of Korea
*yskoh7@jejunu.ac.kr
31 December 2025. pp. 298-309
PDF XML Citation
Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor first identified for its central role in sensing, mediating responses to environmental pollutants, and xenobiotic detoxification. However, recent studies reclassified AhR as a critical regulator of immune responses, barrier integrity, metabolism, and host-microbiota interactions. The receptor has pleiotropic signaling and is involved in canonical and non-canonical pathways in ligand-, tissue-, and context-specific manners that influence transcriptional programs. AhR is broadly distributed in barrier tissues such as the gut, skin, and lung where it controls both mucosal immunity and tissue homeostasis. It plays important roles in several important physiological processes such as epithelial regeneration, cytokine generation, and T cell differentiation. Additionally, AhR senses microbial tryptophan metabolites, which serves as a critical interface between host immunity and the gut microbiota. Its dualistic role as a mediator of both protective and pathological responses emphasizes its complexity in health and disease. Here, we present an overview of the multiple functions of AhR in regulating immunity and maintaining physiological balance, emphasizing its relevance in both health and disease. We further highlight AhR signaling pathways as therapeutic targets for chronic inflammatory, metabolic, and immune-mediated diseases and provide rationale for developing ligand-specific strategies to achieve optimal efficacy and reduced toxicity in clinical applications.

Keywords
Aryl hydrocarbon receptor
Immunity
Health
Disease
Gut microbiota
References
1

Esser C, Rannug A, Stockinger B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 2009;30(9):447-454.

10.1016/j.it.2009.06.005
2

Gutiérrez-Vázquez C, Quintana FJ. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity. 2018;48(1):19-33.

10.1016/j.immuni.2017.12.012
3

Wright EJ, De Castro KP, Joshi AD, Elferink CJ. Canonical and non-canonical aryl hydrocarbon receptor signaling pathways. Curr Opin Toxicol. 2017;2:87-92.

10.1016/j.cotox.2017.01.001
4

Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39(2):372-385.

10.1016/j.immuni.2013.08.003
5

Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI. Cutting edge: activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+CD25+ cells with characteristics of regulatory T cells. J Immunol. 2005;175(7):4184-4188.

10.4049/jimmunol.175.7.4184
6

Huang W, Rui K, Wang X, Peng N, Zhou W, Shi X, et al. The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis. J Autoimmun. 2023;138:103049.

10.1016/j.jaut.2023.103049
7

Coretti L, Buommino E, Lembo F. The aryl hydrocarbon receptor pathway: a linking bridge between the gut microbiome and neurodegenerative diseases. Front Cell Neurosci. 2024;18:1433747.

10.3389/fncel.2024.1433747
8

Hou JJ, Ma AH, Qin YH. Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota. Front Cell Infect Microbiol. 2023;13:1279172.

10.3389/fcimb.2023.1279172
9

Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol. 2003;43:309-334.

10.1146/annurev.pharmtox.43.100901.135828
10

Beamer CA, Shepherd DM. Role of the aryl hydrocarbon receptor (AhR) in lung inflammation. Semin Immunopathol. 2013;35(6):693-704.

10.1007/s00281-013-0391-7
11

Vogel CFA, Van Winkle LS, Esser C, Haarmann-Stemmann T. The aryl hydrocarbon receptor as a target of environmental stressors – Implications for pollution mediated stress and inflammatory responses. Redox Biol. 2020;34:101530.

10.1016/j.redox.2020.101530
12

Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185(6):3190-3198.

10.4049/jimmunol.0903670
13

Rannug A, Rannug U. The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation. Crit Rev Toxicol. 2018;48(7):555-574.

10.1080/10408444.2018.1493086
14

De Juan A, Segura E. Modulation of immune responses by nutritional ligands of aryl hydrocarbon receptor. Front. Immunol. 2021;12:645168.

10.3389/fimmu.2021.645168
15

Wang M, Guo J, Hart AL, Li JV. Indole-3-aldehyde reduces inflammatory responses and restores intestinal epithelial barrier function partially via aryl hydrocarbon receptor (AhR) in experimental colitis models. J Inflamm Res. 2023;16:5845-5864.

10.2147/JIR.S432747
16

Su X, Gao Y, Yang R. Gut microbiota-derived tryptophan metabolites maintain gut and systemic homeostasis. Cells. 2022;11(15):2296.

10.3390/cells11152296
17

Piwowarski JP, Kiss AK, Granica S, Moeslinger T. Urolithins, gut microbiota-derived metabolites of ellagitannins, inhibit LPS-induced inflammation in RAW264.7 murine macrophages. Mol Nutr Food Res. 2015;59(11):2168-2177.

10.1002/mnfr.201500264
18

Marinelli L, Martin-Gallausiaux C, Bourhis JM, Béguet-Crespel F, Blottière HM, Lapaque N, et al. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep. 2019;9(1):643.

10.1038/s41598-018-37019-2
19

Cannon AS, Nagarkatti PS, Nagarkatti M. Targeting AhR as a novel therapeutic modality against inflammatory diseases. Int J Mol Sci. 2021;23(1):288.

10.3390/ijms23010288
20

Mohammadi-Bardbori A, Bengtsson J, Rannug U, Rannug A, Wincent E. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AhR). Chem Res Toxicol. 2012;25(9):1878-1884.

10.1021/tx300169e
21

Zhao B, Degroot DE, Hayashi A, He G, Denison MS. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol Sci. 2010;117(2):393-403.

10.1093/toxsci/kfq217
22

Coelho NR, Tomkiewicz C, Correia MJ, Gonçalves-Dias C, Barouki R, Pereira SA, et al. First evidence of aryl hydrocarbon receptor as a druggable target in hypertension induced by chronic intermittent hypoxia. Pharmacol Res. 2020;159:104869.

10.1016/j.phrs.2020.104869
23

Smith KJ, Murray IA, Tanos R, Tellew J, Boitano AE, Bisson WH, et al. Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther. 2011;338(1):318-327.

10.1124/jpet.110.178392
24

Ciolino HP, Yeh GC. The flavonoid galangin is an inhibitor of CYP1A1 activity and an agonist/antagonist of the aryl hydrocarbon receptor. Br J Cancer. 1999;79(9-10):1340-1346.

10.1038/sj.bjc.6690216
25

Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018;11(4):1024-1038.

10.1038/s41385-018-0019-2
26

Sondermann NC, Faßbender S, Hartung F, Hätälä AM, Rolfes KM, Vogel CFA, et al. Functions of the aryl hydrocarbon receptor (AhR) beyond the canonical AhR/ARNT signaling pathway. Biochem Pharmacol. 2023;208:115371.

10.1016/j.bcp.2022.115371
27

Ishihara Y, Kado SY, Bein KJ, He Y, Pouraryan AA, Urban A, et al. Aryl hydrocarbon receptor signaling synergizes with TLR/NF-κB-signaling for induction of IL-22 through canonical and non-canonical AhR pathways. Front Toxicol. 2022;3:787360.

10.3389/ftox.2021.787360
28

Denison MS, Faber SC. And now for something completely different: diversity in ligand-dependent activation of Ah receptor responses. Curr Opin Toxicol. 2017;2:124-131.

10.1016/j.cotox.2017.01.006
29

Seok SH, Ma ZX, Feltenberger JB, Chen H, Chen H, Scarlett C, et al. Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AhR). J Biol Chem. 2018;293(6):1994-2005.

10.1074/jbc.RA117.000631
30

Evans BR, Karchner SI, Allan LL, Pollenz RS, Tanguay RL, Jenny MJ, et al. Repression of aryl hydrocarbon receptor (AhR) signaling by AhR repressor: role of DNA binding and competition for AhR nuclear translocator. Mol Pharmacol. 2008;73(2):387-398.

10.1124/mol.107.040204
31

Vogel CFA, Haarmann-Stemmann T. The aryl hydrocarbon receptor repressor - More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer. Curr Opin Toxicol. 2017;2:109-119.

10.1016/j.cotox.2017.02.004
32

Xiong R, Shao D, Do S, Chan WK. Activation of chaperone-mediated autophagy inhibits the aryl hydrocarbon receptor function by degrading this receptor in human lung epithelial carcinoma A549 cells. Int J Mol Sci. 2023;24(20):15116.

10.3390/ijms242015116
33

Fernández-Gallego N, Sánchez-Madrid F, Cibrian D. Role of AhR ligands in skin homeostasis and cutaneous inflammation. Cells. 2021;10(11):3176.

10.3390/cells10113176
34

Stockinger B, Veldhoen M, Hirota K. Modulation of Th17 development and function by activation of the aryl hydrocarbon receptor-the role of endogenous ligands. Eur J Immunol. 2009;39(3):652-654.

10.1002/eji.200839134
35

Yasuda T, Takagi T, Asaeda K, Hashimoto H, Kajiwara M, Azuma Y, et al. Urolithin A-mediated augmentation of intestinal barrier function through elevated secretory mucin synthesis. Sci Rep. 2024;14(1):15706.

10.1038/s41598-024-65791-x
36

Ho PP, Steinman L. The aryl hydrocarbon receptor: a regulator of Th17 and Treg cell development in disease. Cell Res. 2008;18(6):605-608.

10.1038/cr.2008.63
37

Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235-238.

10.1038/nature04753
38

Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453(7191):65-71.

10.1038/nature06880
39

Rehman A, Koh Y-S. Impact of ambient particulate matter on the skin’s immune system. J Bacteriol Virol 2022;52(3):83-93.

10.4167/jbv.2022.52.3.083
40

Arooj M, Rehman A, Hyun CL, Rafique A, Kang H-K, Hyun JW et al. Diesel exhaust particulate matter impairs toll-like receptor signaling and host defense against staphylococcal cutaneous infection in mice. Ecotoxicol Environ Saf. 2023;249:114443.

10.1016/j.ecoenv.2022.114443
41

Ehrlich AK, Pennington JM, Bisson WH, Kolluri SK, Kerkvliet NI. TCDD, FICZ, and other high affinity AhR ligands dose-dependently determine the fate of CD4+ T cell differentiation. Toxicol Sci. 2018;161(2):310-320.

10.1093/toxsci/kfx215
42

van Voorhis M, Knopp S, Julliard W, Fechner JH, Zhang X, Schauer JJ, et al. Exposure to atmospheric particulate matter enhances Th17 polarization through the aryl hydrocarbon receptor. PLoS One. 2013;8(12):e82545.

10.1371/journal.pone.0082545
43

Matthews NC, Pfeffer PE, Mann EH, Kelly FJ, Corrigan CJ, Hawrylowicz CM, et al. Urban particulate matter-activated human dendritic cells induce the expansion of potent inflammatory Th1, Th2, and Th17 effector cells. Am J Respir Cell Mol Biol. 2016;54(2):250-262.

10.1165/rcmb.2015-0084OC
44

Castan͂eda AR, Pinkerton KE, Bein KJ, Magan͂a-Méndez A, Yang HT, Vogel CFA, et al. Ambient particulate matter activates the aryl hydrocarbon receptor in dendritic cells and enhances Th17 polarization. Toxicol Lett. 2018;292:85-96.

10.1016/j.toxlet.2018.04.020
45

Matthews NC, Faith A, Pfeffer P, Lu H, Kelly FJ, Hawrylowicz CM, et al. Urban particulate matter suppresses priming of T helper type 1 cells by granulocyte/macrophage colony-stimulating factor-activated human dendritic cells. Am J Respir Cell Mol Biol. 2014;50(2):281-291.

10.1165/rcmb.2012-0465OC
46

O’Driscoll CA, Gallo ME, Hoffmann EJ, Fechner JH, Schauer JJ, Bradfield CA, et al. Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AhR) in vitro. PLoS One. 2018;13(12):e0209690.

10.1371/journal.pone.0209690
Information
  • Publisher :The Korean Society for Microbiology and The Korean Society of Virology
  • Publisher(Ko) :대한미생물학회‧대한바이러스학회
  • Journal Title :JOURNAL OF BACTERIOLOGY AND VIROLOGY
  • Volume : 55
  • No :4
  • Pages :298-309
  • Received Date : 2025-08-17
  • Revised Date : 2025-09-15
  • Accepted Date : 2025-11-07
  • DOI :https://doi.org/10.4167/jbv.2025.55.4.298
Journal Informaiton JOURNAL OF BACTERIOLOGY AND VIROLOGY JOURNAL OF BACTERIOLOGY AND VIROLOGY
  • NRF
  • 임플란트학회 전용 배너
  • KOFST
  • crossref crossmark
  • crossref cited-by
  • crossref funder-registry
  • crosscheck
  • orcid
  • open access
  • ccl
Journal Informaiton Journal Informaiton - close