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Cited by 119Toxic Organic Pollutants ImpactImmunotoxicology and immune responsesImmune Response and Inflammation

Aryl hydrocarbon receptor: Linking environment to immunity

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Cella, Marina, Colonna, Marco·2015·Seminars in Immunology
DOI 10.1016/j.smim.2015.10.002PMC PMC4681659
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Abstract

Mucosal and barrier tissues are unique in that they mediate crosstalk between the host and the surrounding environment, which contains many potentially harmful factors. Therefore, it is critical that cell types present at barrier and mucosal surfaces are equipped with mechanisms to sense changes in the environment and to calibrate their responses accordingly. Aryl Hydrocarbon Receptor (AHR) is a ligand dependent transcription factor well known to generate biological responses to environmental pollutants, such as benzo{a}pyrene and halogenated dioxins. Surprisingly, in the last few years a large body of evidence has shown that AHR is also involved in maintaining homeostasis or in triggering pathology by modulating the biological responses of critical cell types at the barrier and mucosal interfaces. Here, we will review progresses in this field and discuss how targeting AHR activation may impact disease.

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  • Recent studies support the idea that the AHR has a substantial physiological role independent of the adaptive metabolic response and toxicity.

    “In addition to its role as the “dioxin receptor”, recent studies support the idea that the AHR also has a substantial physiological role independent of the adaptive metabolic response and toxicity (Bhaumik & Basu, 2017; Cella & Colonna, 2015; Esser et al., 2009; Gutiérrez-Vázquez & Quintana, 2018; Quintana et al., 2008; Stockinger et al., 2014; Veldhoen et al., 2008).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Cella & Colonna, 2015

  • Recent studies have shown that AHR influences the maintenance of certain resident immune cells, such as innate lymphoid cells in the gut, while also aiding in the orchestration of immune responses such as cytokine production.

    “Recent studies have expanded upon these early characterizations to show that AHR influences the maintenance of certain resident immune cells, such as innate lymphoid cells in the gut, while also aiding in the orchestration of immune responses such as cytokine production (Cella & Colonna, 2015; Eberl et al., 2015; M. Kim & Kim, 2016; Zhou, 2016).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Cella & Colonna, 2015

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References 81 · Cited by 119

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  1. [1]Kewley RJ Whitelaw ML Chapman-Smith A The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int. J. Biochem. Cell Biol 2004 36 189 204 14643885
  2. [2]Gu YZ Hogenesch JB Bradfield CA The PAS superfamily: sensors of environmental and developmental signals. Ann. Rev. Pharmacol. Toxicol 2000 40 519 561 10836146
  3. [3]Nambu JR Lewis JO Wharton KA Jr. Crews ST The Drosophila single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development. Cell 1991 67 1157 1167 1760843
  4. [4]Burbach KM Poland A Bradfield CA Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc. Natl. Acad. Sci. U. S. A 1992 89 8185 8189 1325649 PMC49882
  5. [5]Denison MS Nagy SR Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Ann. Rev. Pharmacol. Toxicol 2003 43 309 334 12540743
  6. [6]Warner M Mocarelli P Brambilla P Wesselink A Patterson DG Jr. Turner WE Serum TCDD and TEQ concentrations among Seveso women, 20 years after the explosion. J. Exp. Sci. Env. Epidem 2014 24 588 594 PMC4031297 24149975
  7. [7]Nguyen LP Bradfield CA The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol 2008 21 102 116 18076143 PMC2572005
  8. [8]Bjeldanes LF Kim JY Grose KR Bartholomew JC Bradfield CA 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. U. S. A 1991 88 9543 9547 1658785 PMC52754
  9. [9]Zhang S Qin C Safe SH Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Env. Health Persp 2003 111 1877 1882 PMC1241760 14644660
  10. [10]Hu Q He G Zhao J Soshilov A Denison MS Zhang A Ginsenosides are novel naturally-occurring aryl hydrocarbon receptor ligands. PloS ONE 2013 8 e66258 23776647 PMC3679084
  11. [11]Rannug U Rannug A Sjoberg U Li H Westerholm R Bergman J Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands. Chem & Biol 1995 2 841 845 8807817
  12. [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 3190 3198 20720200 PMC2952546
  13. [13]Sarsero JP Merino E Yanofsky C A Bacillus subtilis operon containing genes of unknown function senses tRNATrp charging and regulates expression of the genes of tryptophan biosynthesis. Proc. Natl. Acad. Sci. U. S. A 2000 97 2656 2661 10706627 PMC15985
  14. [14]Gaitanis G Magiatis P Stathopoulou K Bassukas ID Alexopoulos EC Velegraki A AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis. J. Inv. Dermatol 2008 128 1620 1625 18219281
  15. [15]Takamura T Harama D Fukumoto S Nakamura Y Shimokawa N Ishimaru K Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. Immunol. Cell Biol 2011 89 817 822 21321579 PMC3257032
  16. [17]Moura-Alves P Fae K Houthuys E Dorhoi A Kreuchwig A Furkert J AhR sensing of bacterial pigments regulates antibacterial defence. Nature 2014 512 387 392 25119038
  17. [18]Esser C Rannug A The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol. Rev 2015 67 259 279 25657351
  18. [19]Di Meglio P Duarte JH Ahlfors H Owens ND Li Y Villanova F Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 2014 40 989 1001 24909886 PMC4067745
  19. [20]Fernandez-Salguero P Pineau T Hilbert DM McPhail T Lee SS Kimura S Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 1995 268 722 726 7732381
  20. [21]Schmidt JV Su GH Reddy JK Simon MC Bradfield CA Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc. Natl. Acad. Sci. U. S. A 1996 93 6731 6736 8692887 PMC39095
  21. [22]Andreola F Fernandez-Salguero PM Chiantore MV Petkovich MP Gonzalez FJ De Luca LM Aryl hydrocarbon receptor knockout mice (AHR−/−) exhibit liver retinoid accumulation and reduced retinoic acid metabolism. Cancer Res 1997 57 2835 2838 9230184
  22. [23]Hauben E Gregori S Draghici E Migliavacca B Olivieri S Woisetschlager M Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. Blood 2008 112 1214 1222 18550851
  23. [24]Lawrence BP Denison MS Novak H Vorderstrasse BA Harrer N Neruda W Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood 2008 112 1158 1165 18270326 PMC2515129
  24. [25]Platzer B Richter S Kneidinger D Waltenberger D Woisetschlager M Strobl H Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J. Immunol 2009 183 66 74 19535631
  25. [26]Boitano AE Wang J Romeo R Bouchez LC Parker AE Sutton SE Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010 329 1345 1348 20688981 PMC3033342
  26. [27]Liu H Ramachandran I Gabrilovich DI Regulation of plasmacytoid dendritic cell development in mice by aryl hydrocarbon receptor. Immunol. Cell Biol 2014 92 200 203 24165981 PMC3945671
  27. [28]Thordardottir S Hangalapura BN Hutten T Cossu M Spanholtz J Schaap N The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells. Stem Cell Develop 2014 23 955 967 24325394
  28. [29]Jux B Kadow S Esser C Langerhans cell maturation and contact hypersensitivity are impaired in aryl hydrocarbon receptor-null mice. J. Immunol 2009 182 6709 6717 19454665
  29. [30]Vogel CF Goth SR Dong B Pessah IN Matsumura F Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem. Bioph. Res. Comm 2008 375 331 335 PMC2583959 18694728
  30. [31]Nguyen NT Kimura A Nakahama T Chinen I Masuda K Nohara K Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl. Acad. Sci. U. S. A 2010 107 19961 19966 21041655 PMC2993339
  31. [32]Song J Clagett-Dame M Peterson RE Hahn ME Westler WM Sicinski RR A ligand for the aryl hydrocarbon receptor isolated from lung. Proc. Natl. Acad. Sci. U. S. A 2002 99 14694 14699 12409613 PMC137481
  32. [33]Quintana FJ Murugaiyan G Farez MF Mitsdoerffer M Tukpah AM Burns EJ An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U. S. A 2010 107 20768 20773 21068375 PMC2996442
  33. [34]Vogel CF Khan EM Leung PS Gershwin ME Chang WL Wu D Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-kappaB. J. Biol. Chem 2014 289 1866 1875 24302727 PMC3894361
  34. [35]Kimura A Naka T Nakahama T Chinen I Masuda K Nohara K Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J. Exp. Med 2009 206 2027 2035 19703987 PMC2737163
  35. [36]Bessede A Gargaro M Pallotta MT Matino D Servillo G Brunacci C Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 2014 511 184 190 24930766 PMC4098076
  36. [37]Opitz CA Litzenburger UM Sahm F Ott M Tritschler I Trump S An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011 478 197 203 21976023
  37. [38]Pilotte L Larrieu P Stroobant V Colau D Dolusic E Frederick R Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. U. S. A 2012 109 2497 2502 22308364 PMC3289319
  38. [39]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 4184 4188 16177056
  39. [41]Quintana FJ Basso AS Iglesias AH Korn T Farez MF Bettelli E Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008 453 65 71 18362915
  40. [42]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 2009 206 43 49 19114668 PMC2626686
  41. [43]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. U. S. A 2008 105 9721 9726 18607004 PMC2474493
  42. [44]Rutz S Noubade R Eidenschenk C Ota N Zeng W Zheng Y Transcription factor c-Maf mediates the TGF-beta-dependent suppression of IL-22 production in T(H)17 cells. Nat. Immunol 2011 12 1238 1245 22001828
  43. [45]Alam MS Maekawa Y Kitamura A Tanigaki K Yoshimoto T Kishihara K Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U. S. A 2010 107 5943 5948 20231432 PMC2851859
  44. [46]Qiu J Guo X Chen ZM He L Sonnenberg GF Artis D Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 2013 39 386 399 23954130 PMC3884586
  45. [48]Ivanov II Atarashi K Manel N Brodie EL Shima T Karaoz U Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009 139 485 498 19836068 PMC2796826
  46. [49]Yang Y Torchinsky MB Gobert M Xiong H Xu M Linehan JL Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 2014 510 152 156 24739972 PMC4128479
  47. [51]Apetoh L Quintana FJ Pot C Joller N Xiao S Kumar D The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol 2010 11 854 861 20676095 PMC2940320
  48. [52]Wu HY Quintana FJ da Cunha AP Dake BT Koeglsperger T Starossom SC In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PloS ONE 2011 6 e23618 21886804 PMC3160310
  49. [53]Gandhi R Kumar D Burns EJ Nadeau M Dake B Laroni A Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat. Immunol 2010 11 846 853 20676092 PMC2929008
  50. [54]Quintana FJ Jin H Burns EJ Nadeau M Yeste A Kumar D Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol 2012 13 770 777 22751139 PMC3541018
  51. [55]Gagliani N Vesely MC Iseppon A Brockmann L Xu H Palm NW Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015 523 221 225 25924064 PMC4498984
  52. [56]Mascanfroni ID Takenaka MC Yeste A Patel B Wu Y Kenison JE Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat. Med 2015 21 638 646 26005855 PMC4476246
  53. [57]Basu R O'Quinn DB Silberger DJ Schoeb TR Fouser L Ouyang W Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 2012 37 1061 1075 23200827 PMC3678257
  54. [58]Ramirez JM Brembilla NC Sorg O Chicheportiche R Matthes T Dayer JM Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur. J. Immunol 2010 40 2450 2459 20706985
  55. [59]Lawrence BP Roberts AD Neumiller JJ Cundiff JA Woodland DL Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung. J. Immunol 2006 177 5819 5828 17056506
  56. [60]Winans B Nagari A Chae M Post CM Ko CI Puga A Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. J. Immunol 2015 194 4446 4457 25810390 PMC4402273
  57. [61]Zaid A Mackay LK Rahimpour A Braun A Veldhoen M Carbone FR Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. U. S. A 2014 111 5307 5312 24706879 PMC3986170
  58. [62]Lockhart E Green AM Flynn JL IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J. Immunol 2006 177 4662 4669 16982905
  59. [63]Duan J Chung H Troy E Kasper DL Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing gamma/delta T cells. Cell Host Microbe 2010 7 140 150 20159619 PMC4048034
  60. [64]Martin B Hirota K Cua DJ Stockinger B Veldhoen M Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 2009 31 321 330 19682928
  61. [65]Li Y Innocentin S Withers DR Roberts NA Gallagher AR Grigorieva EF Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011 147 629 640 21999944
  62. [66]Kadow S Jux B Zahner SP Wingerath B Chmill S Clausen BE Aryl hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in the murine epidermis. J. Immunol 2011 187 3104 3110 21844385
  63. [67]Guo L Junttila IS Paul WE Cytokine-induced cytokine production by conventional and innate lymphoid cells. Trends Immunol 2012 33 598 606 22959641 PMC4799496
  64. [68]Cella M Miller H Song C Beyond NK cells: the expanding universe of innate lymphoid cells. Front. Immunol 2014 5 282 292 24982658 PMC4058828
  65. [69]Diefenbach A Colonna M Koyasu S Development, differentiation, and diversity of innate lymphoid cells. Immunity 2014 41 354 365 25238093 PMC4171710
  66. [70]Eberl G Colonna M Di Santo JP McKenzie AN Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science 2015 348 aaa6566 25999512 PMC5658207
  67. [71]Artis D Spits H The biology of innate lymphoid cells. Nature 2015 517 293 301 25592534
  68. [73]Kiss EA Vonarbourg C Kopfmann S Hobeika E Finke D Esser C Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 2011 334 1561 1565 22033518
  69. [74]Qiu J Heller JJ Guo X Chen ZM Fish K Fu YX The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 2012 36 92 104 22177117 PMC3268875
  70. [75]Hughes T Briercheck EL Freud AG Trotta R McClory S Scoville SD The transcription Factor AHR prevents the differentiation of a stage 3 innate lymphoid cell subset to natural killer cells. Cell Rep 2014 8 150 162 24953655 PMC4133146
  71. [76]Cella M Otero K Colonna M Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc. Natl. Acad. Sci. U. S. A 2010 107 10961 10966 20534450 PMC2890739
  72. [77]Bouskra D Brezillon C Berard M Werts C Varona R Boneca IG Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 2008 456 507 510 18987631
  73. [78]Shin JH Zhang L Murillo-Sauca O Kim J Kohrt HE Bui JD Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U. S. A 2013 110 12391 12396 23836658 PMC3725066
  74. [79]Wagage S John B Krock BL Hall AO Randall LM Karp CL The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J. Immunol 2014 192 1661 1670 24403534 PMC3955958
  75. [80]Kamanaka M Huber S Zenewicz LA Gagliani N Rathinam C O'Connor W Jr. Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J. Exp. Med 2011 208 1027 1040 21518800 PMC3092344

Authors
Cella, M., & Colonna, M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
  • Cella, Marina
  • Colonna, Marco
ORCID
Venue
Seminars in Immunology
Publisher
Elsevier BV
Published
2015-09
Volume
27
Issue
5
Pages
310-314
ISSN
1044-5323 (ISSN-L)
DOI
10.1016/j.smim.2015.10.002
PMC
PMC4681659
OpenAlex
W2158165456
Cited by
119
References
81
Citations by year
2026: 5 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 16 · 2021: 14 · 2020: 10 · 2019: 10 · 2018: 16 · 2017: 12 · 2016: 10
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Seminars in Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Crohn's & Colitis Foundation of America (274415)
  • National Institutes of Health (1U01AI095542, R01DE021255, R21CA16719, RO1 CA176695)
  • National Multiple Sclerosis Society (RG4687A1)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
aryl hydrocarbon receptor, environmental pollutants, benzo[a]pyrene, mucosal immunity, barrier immunity, immune homeostasis
MeSH terms
Animals, Dendritic Cells, Environment, Humans, Immune System, Immunity, Immunity, Innate, Ligands, Organ Specificity, Signal Transduction, Lymphocyte Subsets, Receptors, Aryl Hydrocarbon

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