{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T04:40:13Z","timestamp":1774586413378,"version":"3.50.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,8,1]],"date-time":"2020-08-01T00:00:00Z","timestamp":1596240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"MEXT, Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H06663"],"award-info":[{"award-number":["16H06663"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT, Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K16018"],"award-info":[{"award-number":["18K16018"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2\u2013related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1\u03b1. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.<\/jats:p>","DOI":"10.4049\/jimmunol.2000274","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T20:22:47Z","timestamp":1595276567000},"page":"907-914","source":"Crossref","is-referenced-by-count":26,"title":["NRF2 Augments Epidermal Antioxidant Defenses and Promotes Atopy"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1124-4572","authenticated-orcid":false,"given":"Tatsuya","family":"Ogawa","sequence":"first","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-5427","authenticated-orcid":false,"given":"Yosuke","family":"Ishitsuka","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0166-2658","authenticated-orcid":false,"given":"Yoshiyuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6050-680X","authenticated-orcid":false,"given":"Noriko","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akimasa","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-8496","authenticated-orcid":false,"given":"Yasuhiro","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8254-9176","authenticated-orcid":false,"given":"Rei","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-0773","authenticated-orcid":false,"given":"Naoko","family":"Okiyama","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3643-2879","authenticated-orcid":false,"given":"Yasushi","family":"Suga","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Juntendo University Urayasu Hospital , Urayasu, Chiba 279-0021 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-5880","authenticated-orcid":false,"given":"Dennis R","family":"Roop","sequence":"additional","affiliation":[{"name":"Charles C. Gates Center for Regenerative Medicine, Department of Dermatology, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3062-4872","authenticated-orcid":false,"given":"Manabu","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575 ,","place":["Japan"]},{"name":"Department of Dermatology, Osaka University Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,8,15]]},"reference":[{"key":"2025030417504711000_r1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jaci.2018.10.033","article-title":"Human and computational models of atopic dermatitis: a review and perspectives by an expert panel of the international Eczema council","volume":"143","author":"Eyerich","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030417504711000_r2","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1056\/NEJMra1011040","article-title":"Filaggrin mutations associated with skin and allergic diseases","volume":"365","author":"Irvine","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"2025030417504711000_r3","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.jaci.2014.07.061","article-title":"Peeling off the genetics of atopic dermatitis-like congenital disorders","volume":"134","author":"Samuelov","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030417504711000_r4","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.jaci.2017.04.004","article-title":"Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march","volume":"139","author":"Czarnowicki","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030417504711000_r5","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1084\/jem.189.5.779","article-title":"Cytotoxicity is mandatory for CD8(+) T cell-mediated contact hypersensitivity","volume":"189","author":"Kehren","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025030417504711000_r6","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1172\/JCI59725","article-title":"Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells","volume":"122","author":"Gomez de Ag\u00fcero","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2025030417504711000_r7","doi-asserted-by":"crossref","first-page":"7576","DOI":"10.4049\/jimmunol.0901064","article-title":"The cutaneous biochemical redox barrier: a component of the innate immune defenses against sensitization by highly reactive environmental xenobiotics","volume":"183","author":"Pickard","year":"2009","journal-title":"J. Immunol."},{"key":"2025030417504711000_r8","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1101\/gad.568810","article-title":"Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis","volume":"24","author":"Sch\u00e4fer","year":"2010","journal-title":"Genes Dev."},{"key":"2025030417504711000_r9","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/0092-8674(90)90073-N","article-title":"Identification of a major keratinocyte cell envelope protein, loricrin","volume":"61","author":"Mehrel","year":"1990","journal-title":"Cell"},{"key":"2025030417504711000_r10","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/ng1248","article-title":"Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation","volume":"35","author":"Wakabayashi","year":"2003","journal-title":"Nat. Genet."},{"key":"2025030417504711000_r11","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"2025030417504711000_r12","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.devcel.2012.11.002","article-title":"Amniotic fluid activates the nrf2\/keap1 pathway to repair an epidermal barrier defect in utero","volume":"23","author":"Huebner","year":"2012","journal-title":"Dev. Cell"},{"key":"2025030417504711000_r13","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nri3150","article-title":"Early immune events in the induction of allergic contact dermatitis","volume":"12","author":"Kaplan","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417504711000_r14","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/bbrc.1997.6943","article-title":"An Nrf2\/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements","volume":"236","author":"Itoh","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025030417504711000_r15","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1016\/j.jid.2016.04.022","article-title":"Lce1 family members are Nrf2-target genes that are induced to compensate for the loss of loricrin","volume":"136","author":"Ishitsuka","year":"2016","journal-title":"J. Invest. Dermatol."},{"key":"2025030417504711000_r16","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1093\/intimm\/13.12.1471","article-title":"IL-1 alpha, but not IL-1 beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity","volume":"13","author":"Nakae","year":"2001","journal-title":"Int. Immunol."},{"key":"2025030417504711000_r17","doi-asserted-by":"crossref","first-page":"44765","DOI":"10.1074\/jbc.M208704200","article-title":"Electrophile response element-mediated induction of the cystine\/glutamate exchange transporter gene expression","volume":"277","author":"Sasaki","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2025030417504711000_r18","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.jaci.2007.01.016","article-title":"Glutathione depletion inhibits dendritic cell maturation and delayed-type hypersensitivity: implications for systemic disease and immunosenescence","volume":"119","author":"Kim","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030417504711000_r19","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.4049\/jimmunol.1801065","article-title":"Cutting edge: Nrf2 regulates neutrophil recruitment and accumulation in skin during contact hypersensitivity","volume":"202","author":"Helou","year":"2019","journal-title":"J. Immunol."},{"key":"2025030417504711000_r20","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1111\/1523-1747.ep12325538","article-title":"Immediate-type hypersensitivity response followed by a late reaction is induced by repeated epicutaneous application of contact sensitizing agents in mice","volume":"105","author":"Kitagaki","year":"1995","journal-title":"J. Invest. Dermatol."},{"key":"2025030417504711000_r21","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ni.3123","article-title":"Control of adaptive immunity by the innate immune system","volume":"16","author":"Iwasaki","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025030417504711000_r22","first-page":"747","article-title":"Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome","volume":"137","author":"Allen","year":"2001","journal-title":"Arch. Dermatol."},{"key":"2025030417504711000_r23","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.jaci.2012.02.036","article-title":"Update on risk factors for food allergy","volume":"129","author":"Lack","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030417504711000_r24","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1111\/1523-1747.ep12384093","article-title":"Protective effect of N-acetylcysteine in hapten-induced irritant and contact hypersensitivity reactions","volume":"102","author":"Senaldi","year":"1994","journal-title":"J. Invest. Dermatol."},{"key":"2025030417504711000_r25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/emm.1999.2","article-title":"Bricks and mortar of the epidermal barrier","volume":"31","author":"Nemes","year":"1999","journal-title":"Exp. Mol. Med."},{"key":"2025030417504711000_r26","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/intimm\/dxv013","article-title":"Dissecting the formation, structure and barrier function of the stratum corneum","volume":"27","author":"Matsui","year":"2015","journal-title":"Int. Immunol."},{"key":"2025030417504711000_r27","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1093\/molbev\/msu251","article-title":"Evolutionary origin and diversification of epidermal barrier proteins in amniotes","volume":"31","author":"Strasser","year":"2014","journal-title":"Mol. Biol. Evol."},{"key":"2025030417504711000_r28","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1016\/j.jid.2018.06.164","article-title":"Loricrin confers photoprotective function against UVB in corneocytes","volume":"138","author":"Ishitsuka","year":"2018","journal-title":"J. Invest. Dermatol."},{"key":"2025030417504711000_r29","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1084\/jem.20062211","article-title":"Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells","volume":"204","author":"Allakhverdi","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030417504711000_r30","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1016\/j.bbamem.2011.08.012","article-title":"Lipophilic penetration enhancers and their impact to the bilayer structure of stratum corneum lipid model membranes: neutron diffraction studies based on the example oleic acid","volume":"1808","author":"Engelbrecht","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030417504711000_r31","doi-asserted-by":"crossref","first-page":"5826","DOI":"10.4049\/jimmunol.180.9.5826","article-title":"Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization","volume":"180","author":"Watanabe","year":"2008","journal-title":"J. Immunol."},{"key":"2025030417504711000_r32","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.immuni.2008.06.017","article-title":"Plasmacytoid dendritic cells mediate oral tolerance","volume":"29","author":"Goubier","year":"2008","journal-title":"Immunity"},{"key":"2025030417504711000_r33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nri2940","article-title":"Tissue-based class control: the other side of tolerance","volume":"11","author":"Matzinger","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417504711000_r34","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/s41590-018-0161-8","article-title":"Epithelial damage and tissue \u03b3\u03b4 T cells promote a unique tumor-protective IgE response","volume":"19","author":"Crawford","year":"2018","journal-title":"Nat. Immunol."},{"key":"2025030417504711000_r35","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1172\/JCI89820","article-title":"Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy","volume":"127","author":"Cunningham","year":"2017","journal-title":"J. Clin. Invest."},{"key":"2025030417504711000_r36","doi-asserted-by":"crossref","first-page":"8293","DOI":"10.1158\/0008-5472.CAN-06-0300","article-title":"Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL\/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2","volume":"66","author":"Xu","year":"2006","journal-title":"Cancer Res."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/4\/907\/61880452\/ji2000274.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/205\/4\/907\/61880452\/ji2000274.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T18:03:08Z","timestamp":1741111388000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/205\/4\/907\/7930975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,8,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2000274","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,8]]}}}