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Environmental pollutants and the immune response

Nature Immunology volume 21, pages 1486–1495 (2020)Cite this article

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Abstract

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1–NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor–response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

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Fig. 1: Differential responses of the body to low-dose and high-dose environmental electrophiles.
Fig. 2: The AHR and KEAP1–NRF2 system sense environmental chemicals and regulate the expression of detoxifying genes.
Fig. 3: The AHR and KEAP1–NRF2 system.

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References

  1. Landrigan, P. J. et al. The Lancet Commission on pollution and health. Lancet 391, 462–512 (2018).

    PubMed  Google Scholar 

  2. Smith, K. R. & Ezzati, M. How environmental health risks change with development: the epidemiologic and environmental risk transitions revisited. Annu. Rev. Environ. Resour. 30, 291–333 (2005).

    Google Scholar 

  3. GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1659–1724 (2016).

    Google Scholar 

  4. Luster, M. I. A historical perspective of immunotoxicology. J. Immunotoxicol. 11, 197–202 (2014).

    CAS  PubMed  Google Scholar 

  5. Luster, M. I., Portier, C., Pait, D. G. & Germolec, D. R. Use of animal studies in risk assessment for immunotoxicology. Toxicology 92, 229–243 (1994).

    CAS  PubMed  Google Scholar 

  6. Gleichmann, E., Kimber, I. & Purchase, I. F. H. Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system. Arch. Toxicol. 63, 257–273 (1989).

    CAS  PubMed  Google Scholar 

  7. Bennett, P. M. et al. Exposure to heavy metals and infectious disease mortality in harbour porpoises from England and Wales. Environ. Pollut. 112, 33–40 (2001).

    CAS  PubMed  Google Scholar 

  8. Germolec, D. et al. Immunotoxicology: a brief history, current status and strategies for future immunotoxicity assessment. Curr. Opin. Toxicol. 5, 55–59 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. Inadera, H. The immune system as a target for environmental chemicals: xenoestrogens and other compounds. Toxicol. Lett. 164, 191–206 (2006).

    CAS  PubMed  Google Scholar 

  10. Fries, G. F. in Reviews of Environmental Contamination and Toxicology Vol. 141 (eds. Ware, G. W. & Gunther, F. A.) 71–109 (Springer, 1995).

  11. Cambra-López, M., Aarnink, A. J. A., Zhao, Y., Calvet, S. & Torres, A. G. Airborne particulate matter from livestock production systems: a review of an air pollution problem. Environ. Pollut. 158, 1–17 (2010).

    PubMed  Google Scholar 

  12. Derraik, J. G. B. The pollution of the marine environment by plastic debris: a review. Mar. Pollut. Bull. 44, 842–852 (2002).

    CAS  PubMed  Google Scholar 

  13. Totlandsdal, A. I. et al. Differential effects of the particle core and organic extract of diesel exhaust particles. Toxicol. Lett. 208, 262–268 (2012).

    CAS  PubMed  Google Scholar 

  14. Foth, H., Kahl, R. & Kahl, G. F. Pharmacokinetics of low doses of benzo[a]pyrene in the rat. Food Chem. Toxicol. 26, 45–51 (1988).

    CAS  PubMed  Google Scholar 

  15. Kao, J., Patterson, F. K. & Hall, J. Skin penetration and metabolism of topically applied chemicals in six mammalian species, including man: an in vitro study with benzo[a]pyrene and testosterone. Toxicol. Appl. Pharmacol. 81, 502–516 (1985).

    CAS  PubMed  Google Scholar 

  16. Morgenstern, V. et al. Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. Am. J. Respir. Crit. Care Med. 177, 1331–1337 (2008).

    PubMed  Google Scholar 

  17. Horne, B. D. et al. Short-term elevation of fine particulate matter air pollution and acute lower respiratory infection. Am. J. Respir. Crit. Care Med. 198, 759–766 (2018).

    PubMed  Google Scholar 

  18. McCreanor, J. et al. Respiratory effects of exposure to diesel traffic in persons with asthma. N. Engl. J. Med. 357, 2348–2358 (2007).

    CAS  PubMed  Google Scholar 

  19. Jedrychowski, W. A. et al. Intrauterine exposure to polycyclic aromatic hydrocarbons, fine particulate matter and early wheeze. Prospective birth cohort study in 4‐year olds. Pediatr. Allergy Immunol. 21, e723–e732 (2010).

    PubMed  PubMed Central  Google Scholar 

  20. Perzanowski, M. S. et al. Early-life cockroach allergen and polycyclic aromatic hydrocarbon exposures predict cockroach sensitization among inner-city children. J. Allergy Clin. Immunol. 131, 886–893 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weisglas-Kuperus, N., Vreugdenhil, H. J. I. & Mulder, P. G. H. Immunological effects of environmental exposure to polychlorinated biphenyls and dioxins in Dutch school children. Toxicol. Lett. 149, 281–285 (2004).

    CAS  PubMed  Google Scholar 

  22. Türk Börü, Ü., Bölük, C., Taşdemir, M., Gezer, T. & Serim, V. A. Air pollution, a possible risk factor for multiple sclerosis. Acta Neurol. Scand. 141, 431–437 (2020).

    PubMed  Google Scholar 

  23. Hidaka, T. et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nat. Immunol. 18, 64–73 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Brennecke, D., Duarte, B., Paiva, F., Caçador, I. & Canning-Clode, J. Microplastics as vector for heavy metal contamination from the marine environment. Estuar. Coast. Shelf Sci. 178, 189–195 (2016).

    CAS  Google Scholar 

  26. Gulland, F. M. D. & Hall, A. J. Is marine mammal health deteriorating? Trends in the global reporting of marine mammal disease. Ecohealth 4, 135–150 (2007).

    Google Scholar 

  27. Bakir, A., Rowland, S. J. & Thompson, R. C. Competitive sorption of persistent organic pollutants onto microplastics in the marine environment. Mar. Pollut. Bull. 64, 2782–2789 (2012).

    CAS  PubMed  Google Scholar 

  28. Fent, K. Ecotoxicology of organotin compounds. Crit. Rev. Toxicology 26, 3–117 (1996).

    Google Scholar 

  29. Snoeij, N. J., Penninks, A. H. & Seinen, W. Dibutyltin and tributyltin compounds induce thymus atrophy in rats due to a selective action on thymic lymphoblasts. Int. J. Immunopharmacol. 10, 891–899 (1988).

    CAS  PubMed  Google Scholar 

  30. Kato, T., Tada-Oikawa, S., Wang, L., Murata, M. & Kuribayashi, K. Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation. Toxicol. Appl. Pharmacol. 273, 10–18 (2013).

    CAS  PubMed  Google Scholar 

  31. Lee, M. H. et al. Enhanced interleukin‐4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen‐primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor‐AT and Ca2+. Immunology 109, 76–86 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bauer, S. M. et al. The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. Toxicol. Sci. 130, 82–93 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nakajima, Y., Goldblum, R. M. & Midoro-Horiuti, T. Fetal exposure to bisphenol A as a risk factor for the development of childhood asthma: an animal model study. Environ. Health 11, 8 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Jakober, C. A. et al. Quinone emissions from gasoline and diesel motor vehicles. Environ. Sci. Technol. 41, 4548–4554 (2007).

    CAS  PubMed  Google Scholar 

  35. Spengler, J. D. & Sexton, K. Indoor air pollution: a public health perspective. Science 221, 9–17 (1983).

    CAS  PubMed  Google Scholar 

  36. Hecht, S. S. Tobacco smoke carcinogens and lung cancer. J. Natl Cancer Inst. 91, 1194–1210 (1999).

    CAS  PubMed  Google Scholar 

  37. Kumagai, Y. & Abiko, Y. Environmental electrophiles: protein adducts, modulation of redox signaling, and interaction with persulfides/polysulfides. Chem. Res. Toxicol. 30, 203–219 (2017).

    CAS  PubMed  Google Scholar 

  38. Pearson, R. G. Hard and soft acids and bases. J. Am. Chem. Soc. 85, 3533–3539 (1963).

    CAS  Google Scholar 

  39. Kumagai, Y. & Sumi, D. Arsenic: signal transduction, transcription factor, and biotransformation involved in cellular response and toxicity. Annu. Rev. Pharmacol. Toxicol. 47, 243–262 (2007).

    CAS  PubMed  Google Scholar 

  40. Saito, M. et al. Molecular mechanisms of nickel allergy. Int. J. Mol. Sci. 17, 202 (2016).

    PubMed Central  Google Scholar 

  41. Sharma, R. K. & Agrawal, M. Biological effects of heavy metals: an overview. J. Environ. Biol. 26, 301–313 (2005).

    CAS  PubMed  Google Scholar 

  42. Carter, J. D., Ghio, A. J., Samet, J. M. & Devlin, R. B. Cytokine production by human airway epithelial cells after exposure to an air pollution particle is metal-dependent. Toxicol. Appl. Pharmacol. 146, 180–188 (1997).

    CAS  PubMed  Google Scholar 

  43. Lehmann, I., Sack, U. & Lehmann, J. Metal ions affecting the immune system. Met. Ions Life Sci. 8, 157–185 (2011).

    CAS  PubMed  Google Scholar 

  44. Gauthier, P. T., Norwood, W. P., Prepas, E. E. & Pyle, G. G. Metal–PAH mixtures in the aquatic environment: a review of co-toxic mechanisms leading to more-than-additive outcomes. Aquat. Toxicol. 154, 253–269 (2014).

    CAS  PubMed  Google Scholar 

  45. Lawrence, D. A. & McCabe, M. J. Jr. Immunomodulation by metals. Int. Immunopharmacol. 2, 293–302 (2002).

    CAS  PubMed  Google Scholar 

  46. Ewers, U., Stiller-Winkler, R. & Idel, H. Serum immunoglobulin, complement C3, and salivary IgA levels in lead workers. Environ. Res. 29, 351–357 (1982).

    CAS  PubMed  Google Scholar 

  47. Hughes, M. F., Beck, B. D., Chen, Y., Lewis, A. S. & Thomas, D. J. Arsenic exposure and toxicology: a historical perspective. Toxicol. Sci. 123, 305–332 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rahman, A. et al. Association of arsenic exposure during pregnancy with fetal loss and infant death: a cohort study in Bangladesh. Am. J. Epidemiol. 165, 1389–1396 (2007).

    PubMed  Google Scholar 

  49. Moore, S. E. et al. Early‐life nutritional and environmental determinants of thymic size in infants born in rural Bangladesh. Acta Paediatr. 98, 1168–1175 (2009).

    PubMed  PubMed Central  Google Scholar 

  50. Kirschvink, N. et al. Airway inflammation in cadmium-exposed rats is associated with pulmonary oxidative stress and emphysema. Free Radic. Res. 40, 241–250 (2006).

    CAS  PubMed  Google Scholar 

  51. Ganguly, K., Levänen, B., Palmberg, L., Åkesson, A. & Lindén, A. Cadmium in tobacco smokers: a neglected link to lung disease? Eur. Respir. Rev. 27, 170122 (2018).

    PubMed  Google Scholar 

  52. Leffel, E. K., Wolf, C., Poklis, A. & White, K. L. Jr. Drinking water exposure to cadmium, an environmental contaminant, results in the exacerbation of autoimmune disease in the murine model. Toxicology 188, 233–250 (2003).

    CAS  PubMed  Google Scholar 

  53. Sapin, C., Druet, E. & Druet, P. Induction of anti-glomerular basement membrane antibodies in the Brown–Norway rat by mercuric chloride. Clin. Exp. Immunol. 28, 173–179 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hudson, C. A., Cao, L., Kasten-Jolly, J., Kirkwood, J. N. & Lawrence, D. A. Susceptibility of lupus-prone NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms. J. Toxicol. Environ. Health A 66, 895–918 (2003).

    CAS  PubMed  Google Scholar 

  55. Liska, D. J. The detoxification enzyme systems. Altern. Med. Rev. 3, 187–198 (1998).

    CAS  PubMed  Google Scholar 

  56. Talalay, P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12, 5–11 (2000).

    CAS  PubMed  Google Scholar 

  57. Vašák, M. Advances in metallothionein structure and functions. J. Trace Elem. Med. Biol. 19, 13–17 (2005).

    PubMed  Google Scholar 

  58. Flora, S. J. S. Metal poisoning: threat and management. Al Ameen J. Med. Sci. 2, 4–26 (2009).

    CAS  Google Scholar 

  59. Waxman, D. J. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369, 11–23 (1999).

    CAS  PubMed  Google Scholar 

  60. Yamamoto, M., Kensler, T. W. & Motohashi, H. The KEAP1–NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169–1203 (2018).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  62. Miao, W., Hu, L., Scrivens, P. J. & Batist, G. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J. Biol. Chem. 280, 20340–20348 (2005).

    CAS  PubMed  Google Scholar 

  63. Shin, S. et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol. Cell. Biol. 27, 7188–7197 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Denis, M., Cuthill, S., Wikström, A.-C., Poellinger, L. & Gustafsson, J.-Å. 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).

    CAS  PubMed  Google Scholar 

  65. 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).

    CAS  PubMed  Google Scholar 

  66. 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).

    CAS  PubMed  Google Scholar 

  67. Durrin, L. K. & Whitlock, J. P. Jr. In situ protein-DNA interactions at a dioxin-responsive enhancer associated with the cytochrome P1-450 gene. Mol. Cell. Biol. 7, 3008–3011 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kerkvliet, N. I. & Brauner, J. A. Flow cytometric analysis of lymphocyte subpopulations in the spleen and thymus of mice exposed to an acute immunosuppressive dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Environ. Res. 52, 146–154 (1990).

    CAS  PubMed  Google Scholar 

  69. De Heer, C. et al. Time course of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced thymic atrophy in the Wistar rat. Toxicol. Appl. Pharmacol. 128, 97–104 (1994).

    PubMed  Google Scholar 

  70. McMillan, B. J., McMillan, S. N., Glover, E. & Bradfield, C. A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces premature activation of the KLF2 regulon during thymocyte development. J. Biol. Chem. 282, 12590–12597 (2007).

    CAS  PubMed  Google Scholar 

  71. Temchura, V. V., Frericks, M., Nacken, W. & Esser, C. Role of the aryl hydrocarbon receptor in thymocyte emigration in vivo. Eur. J. Immunol. 35, 2738–2747 (2005).

    CAS  PubMed  Google Scholar 

  72. Feingold, B. J. et al. A niche for infectious disease in environmental health: rethinking the toxicological paradigm. Environ. Health Perspect. 118, 1165–1172 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    CAS  PubMed  Google Scholar 

  74. Hori, S., Takahashi, T. & Sakaguchi, S. Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv. Immunol. 81, 331–371 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  77. Kerkvliet, N. I. et al. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1, 539–547 (2009).

    CAS  PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Singh, N. P. et al. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS ONE 6, e23522 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wu, H. Y. et al. In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PLoS ONE 6, e23618 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    CAS  PubMed  Google Scholar 

  87. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Ann. Rev. Immunol. 27, 485–517 (2009).

    CAS  Google Scholar 

  88. Talbot, J. et al. Smoking-induced aggravation of experimental arthritis is dependent of aryl hydrocarbon receptor activation in Th17 cells. Arthritis Res. Ther. 20, 119 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  93. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  95. Chu, I., Dick, D., Bronaugh, R. & Tryphonas, L. Skin reservoir formation and bioavailability of dermally administered chemicals in hairless guinea pigs. Food Chem. Toxicology 34, 267–276 (1996).

    CAS  Google Scholar 

  96. Alexandrov, K., Rojas, M. & Satarug, S. The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation. Toxicol. Lett. 198, 63–68 (2010).

    CAS  PubMed  Google Scholar 

  97. Kuratsune, M., Yoshimura, T., Matsuzaka, J. & Yamaguchi, A. Yusho, a poisoning caused by rice oil contaminated with polychlorinated biphenyls. HSMHA Health Rep. 86, 1083–1091 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Horne, B. D. et al. Short-term elevation of fine particulate matter air pollution and acute lower respiratory infection. Am. J. Respir. Crit. Care Med. 198, 759–766 (2018).

    PubMed  Google Scholar 

  99. Morgenstern, V. et al. Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. Am. J. Respir. Crit. Care Med. 177, 1331–1337 (2008).

    PubMed  Google Scholar 

  100. Tauchi, M. et al. Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. Mol. Cell. Biol. 25, 9360–9368 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Edamitsu, T., Taguchi, K., Kobayashi, E. H., Okuyama, R. & Yamamoto, M. Aryl hydrocarbon receptor directly regulates artemin gene expression. Mol. Cell. Biol. 39, e00190-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  102. Li, M. et al. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc. Natl Acad. Sci. USA 102, 14795–14800 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Yoo, J. et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Imai, Y. et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc. Natl Acad. Sci. USA 110, 13921–13926 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Itoh, K. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322 (1997).

    CAS  PubMed  Google Scholar 

  106. Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Kobayashi, A. et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24, 7130–7139 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kobayashi, A. et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol. Cell. Biol. 26, 221–229 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Iso, T., Suzuki, T., Baird, L. & Yamamoto, M. Absolute amounts and status of the Nrf2-Keap1-Cul3 complex within cells. Mol. Cell. Biol. 36, 3100–3112 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. McMahon, M., Lamont, D. J., Beattie, K. A. & Hayes, J. D. Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc. Natl Acad. Sci. USA 107, 18838–18843 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Suzuki, T. et al. Molecular mechanism of cellular oxidative stress sensing by Keap1. Cell Rep. 28, 746–758.e4 (2019).

    CAS  PubMed  Google Scholar 

  112. Suzuki, T., Motohashi, H. & Yamamoto, M. Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol. Sci. 34, 340–346 (2013).

    CAS  PubMed  Google Scholar 

  113. Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).

    CAS  PubMed  Google Scholar 

  114. Uruno, A. et al. Nrf2-mediated regulation of skeletal muscle glycogen metabolism. Mol. Cell. Biol. 36, 1655–1672 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hirotsu, Y. et al. Nrf2–MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 40, 10228–10239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Itoh, K. et al. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Δ12,14-prostaglandin J2. Mol. Cell. Biol. 24, 36–45 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ishii, Y. et al. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J. Immunol. 175, 6968–6975 (2005).

    CAS  PubMed  Google Scholar 

  118. Iizuka, T. et al. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 10, 1113–1125 (2005).

    CAS  PubMed  Google Scholar 

  119. Cho, H.-Y., Reddy, S. P. M., Yamamoto, M. & Kleeberger, S. R. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 18, 1258–1260 (2004).

    CAS  PubMed  Google Scholar 

  120. Thimmulappa, R. K. et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Invest. 116, 984–995 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yoh, K. et al. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int. 60, 1343–1353 (2001).

    CAS  PubMed  Google Scholar 

  122. Okada, K. et al. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J. Gastroenterol. 47, 924–935 (2012).

    PubMed  Google Scholar 

  123. Sharma, R. S. et al. Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacologic activation of Nrf2 (NF-E2 p45-related factor 2). Cell. Mol. Gastroenterol. Hepatol. 5, 367–398 (2018).

    PubMed  Google Scholar 

  124. Hayashi, M. et al. Whole-body in vivo monitoring of inflammatory diseases exploiting human interleukin 6-luciferase transgenic mice. Mol. Cell. Biol. 35, 3590–3601 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Suzuki, T. et al. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice. Mol. Cell. Biol. 37, e00063–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Nagashima, R. et al. Nrf2 suppresses allergic lung inflammation by attenuating the type 2 innate lymphoid cell response. J. Immunol. 202, 1331–1339 (2019).

    CAS  PubMed  Google Scholar 

  127. Yagishita, Y., Uruno, A., Chartoumpekis, D. V., Kensler, T. W. & Yamamoto, M. Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice. J. Endocrinol. https://doi.org/10.1530/JOE-18-0355 (2019).

  128. Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

    CAS  PubMed  Google Scholar 

  129. Goven, D. et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 63, 916–924 (2008).

    CAS  PubMed  Google Scholar 

  130. Suzuki, M. et al. Down-regulated NF-E2–related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 39, 673–682 (2008).

    CAS  PubMed  Google Scholar 

  131. Kong, X. et al. Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. Am. J. Respir. Crit. Care Med. 184, 928–938 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Keleku-Lukwete, N. et al. Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. Blood Adv. 3, 1285–1297 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P. & Malik, A. B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–1167 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Keleku-Lukwete, N. et al. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc. Natl Acad. Sci. USA 112, 12169–12174 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Nagai, N. et al. Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic. Biol. Med. 47, 300–306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Higashi, C. et al. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur. J. Pharmacol. 802, 76–84 (2017).

    CAS  PubMed  Google Scholar 

  139. Dayalan Naidu, S. et al. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Sci. Rep. 8, 8037 (2018).

    PubMed  PubMed Central  Google Scholar 

  140. Uruno, A. et al. Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer’s disease model mice. Mol. Cell. Biol. 40, e00467-19 (2020).

    PubMed  PubMed Central  Google Scholar 

  141. Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Turley, A. E., Zagorski, J. W. & Rockwell, C. E. The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells. Cytokine 71, 289–295 (2015).

    CAS  PubMed  Google Scholar 

  143. Rockwell, C. E., Zhang, M., Fields, P. E. & Klaassen, C. D. Th2 skewing by activation of Nrf2 in CD4+ T cells. J. Immunol. 188, 1630–1637 (2012).

    CAS  PubMed  Google Scholar 

  144. Noel, S. et al. T lymphocyte–specific activation of Nrf2 protects from AKI. J. Am. Soc. Nephrol. 26, 2989–3000 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Sireesh, D., Dhamodharan, U., Ezhilarasi, K., Vijay, V. & Ramkumar, K. M. Association of NF-E2 related factor 2 (Nrf2) and inflammatory cytokines in recent onset type 2 diabetes mellitus. Sci. Rep. 8, 5126 (2018).

    PubMed  PubMed Central  Google Scholar 

  146. Zhao, M. et al. Nuclear factor erythroid 2-related factor 2 deficiency exacerbates lupus nephritis in B6/lpr mice by regulating Th17 cell function. Sci. Rep. 6, 38619 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Nadeem, A. et al. Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice. Behav. Brain Res. 364, 213–224 (2019).

    CAS  PubMed  Google Scholar 

  148. Pareek, T. K. et al. Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci. Rep. 1, 201 (2011).

    PubMed  PubMed Central  Google Scholar 

  149. Li, B. et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp. Neurol. 250, 239–249 (2013).

    CAS  PubMed  Google Scholar 

  150. Wu, Q. et al. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J. Immunol. 198, 3069–3080 (2017).

    CAS  PubMed  Google Scholar 

  151. Dinkova-Kostova, A. T. et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc. Natl Acad. Sci. USA 102, 4584–4589 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Honda, T. et al. Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages. J. Med. Chem. 43, 4233–4246 (2000).

    CAS  PubMed  Google Scholar 

  153. Sporn, M. B. et al. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J. Nat. Prod. 74, 537–545 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    PubMed  PubMed Central  Google Scholar 

  155. Zhang, Y., Talalay, P., Cho, C. G. & Posner, G. H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc. Natl Acad. Sci. USA 89, 2399–2403 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fahey, J. W., Zhang, Y. & Talalay, P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl Acad. Sci. USA 94, 10367–10372 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Bent, S. et al. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol. Autism 9, 35 (2018).

    PubMed  PubMed Central  Google Scholar 

  158. Kensler, T. W. et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis 33, 101–107 (2012).

    CAS  PubMed  Google Scholar 

  159. Chen, J.-G. et al. Dose-dependent detoxication of the airborne pollutant benzene in a randomized trial of broccoli sprout beverage in Qidong, China. Am. J. Clin. Nutr. 110, 675–684 (2019).

    PubMed  PubMed Central  Google Scholar 

  160. Yagishita, Y., Fahey, J. W., Dinkova-Kostova, A. T. & Kensler, T. W. Broccoli or sulforaphane: is it the source or dose that matters? Molecules 24, 3595 (2019).

    Google Scholar 

  161. Takaya, K. et al. Validation of the multiple sensor mechanism of the KEAP1–NRF2 system. Free Radic. Biol. Med. 53, 817–827 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Cleasby, A. et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE 9, e98896 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. Saito, R. et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol. Cell. Biol. 36, 271–284 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Jiang, Z.-Y. et al. Discovery of potent Keap1–Nrf2 protein–protein interaction inhibitor based on molecular binding determinants analysis. J. Med. Chem. 57, 2736–2745 (2014).

    CAS  PubMed  Google Scholar 

  165. Lazzara, P. R. et al. Isoquinoline Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (KEAP1–NRF2) inhibitors with high metabolic stability. J. Med. Chem. 63, 6547–6560 (2020).

    CAS  PubMed  Google Scholar 

  166. Yamamoto, T. et al. Identification of polymorphisms in the promoter region of the human NRF2 gene. Biochem. Biophys. Res. Commun. 321, 72–79 (2004).

    CAS  PubMed  Google Scholar 

  167. Marzec, J. M. et al. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 21, 2237–2246 (2007).

    CAS  PubMed  Google Scholar 

  168. Cho, H.-Y. et al. Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am. J. Respir. Cell Mol. Biol. 26, 42–51 (2002).

    CAS  PubMed  Google Scholar 

  169. Arisawa, T. et al. Nrf2 gene promoter polymorphism is associated with ulcerative colitis in a Japanese population. Hepatogastroenterology 55, 394–397 (2008).

    CAS  PubMed  Google Scholar 

  170. Arisawa, T. et al. The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis. Int. J. Mol. Med. 19, 143–148 (2007).

    CAS  PubMed  Google Scholar 

  171. Hua, C.-C. et al. Functional haplotypes in the promoter region of transcription factor Nrf2 in chronic obstructive pulmonary disease. Dis. Markers 28, 185–193 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Suzuki, T. et al. Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Mol. Cell. Biol. 33, 2402–2412 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Pavlova, S. I. & Tao, L. Induction of vaginal Lactobacillus phages by the cigarette smoke chemical benzo[a]pyrene diol epoxide. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 466, 57–62 (2000).

    CAS  Google Scholar 

  174. Dean, J. H. et al. Selective immunosuppression resulting from exposure to the carcinogenic congener of benzopyrene in B6C3F1 mice. Clin. Exp. Immunol. 52, 199–206 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Ritz, B., Heinrich, J., Wjst, M., Wichmann, E. & Krause, C. Effect of cadmium body burden on immune response of school children. Arch. Environ. Health 53, 272–280 (1998).

    CAS  PubMed  Google Scholar 

  176. Kozul, C. D., Ely, K. H., Enelow, R. I. & Hamilton, J. W. Low-dose arsenic compromises the immune response to influenza A infection in vivo. Environ. Health Perspect. 117, 1441–1447 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Queiroz, M. L. S. & Dantas, D. C. M. T lymphocytes in mercury-exposed workers. Immunopharmacol. Immunotoxicol. 19, 499–510 (1997).

    CAS  PubMed  Google Scholar 

  178. Cook, J. A., Hoffmann, E. O. & Di Luzio, N. R. Influence of lead and cadmium on the susceptibility of rats to bacterial challenge. Proc. Soc. Exp. Biol. Med. 150, 741–747 (1975).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank T. O’Connor at Trinity College Dublin for critical reading and professional editing of the manuscript. This work was supported in part by MEXT/JSPS KAKENHI (19H05649 to M. Y. and 17KK0183 and 19K07340 to T. S.), the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under grant no. JP20am0101095, the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) from AMED under grant no. JP20cm0106101, the Core Research for Evolutional Science and Technology (CREST) (chronic inflammation) from AMED, and the Takeda Science Foundation (T.S.).

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  1. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

    Takafumi Suzuki, Takanori Hidaka & Masayuki Yamamoto

  2. Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    Yoshito Kumagai

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Suzuki, T., Hidaka, T., Kumagai, Y. et al. Environmental pollutants and the immune response. Nat Immunol 21, 1486–1495 (2020). https://doi.org/10.1038/s41590-020-0802-6

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