Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis

Masutaka Furue, Akiko Hashimoto-Hachiya, Gaku Tsuji, Masutaka Furue, Akiko Hashimoto-Hachiya, Gaku Tsuji

Abstract

The aryl hydrocarbon receptor (AHR)/AHR-nuclear translocator (ARNT) system is a sensitive sensor for small molecular, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. AHR/ARNT are abundantly expressed in the skin. Once activated, the AHR/ARNT axis strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. In addition, AHR activation induces oxidative stress. However, some AHR ligands simultaneously activate the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. The immunoregulatory system governing T-helper 17/22 (Th17/22) and T regulatory cells (Treg) is also regulated by the AHR system. Notably, AHR agonists, such as tapinarof, are currently used as therapeutic agents in psoriasis and atopic dermatitis. In this review, we summarize recent topics on AHR related to atopic dermatitis and psoriasis.

Keywords: Th17; Th22; Treg; antioxidants; aryl hydrocarbon receptor (AHR); aryl hydrocarbon receptor-nuclear translocator (ARNT); atopic dermatitis; filaggrin; nuclear factor-erythroid 2-related factor-2 (NRF2); psoriasis; reactive oxygen species; skin barrier; tapinarof.

Conflict of interest statement

The authors have no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Aryl hydrocarbon receptor (AHR) signal and action points of tapinarof (red words and arrows). AHR is a promiscuous chemical sensor that is activated by various oxidative and antioxidative ligands. Once activated, cytoplasmic AHR translocates into the nucleus where it heterodimerizes with an AHR-nuclear translocator (ARNT) and then induces the transcription of AHR-responsive genes such as cytochrome P450 1A1 (CYP1A1). CYP1A1 degrades AHR ligands. Some ligands such as dioxins are chemically stable and long-lived. Therefore, CYP1A1 generates high amounts of reactive oxygen species (ROS) after sustained efforts to degrade them. Some antioxidative AHR ligands activate nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor, which upregulates gene expression of various antioxidative enzymes, such as heme oxygenase 1 (HMOX1), NAD(P)H dehydrogenase, and quinone 1 (NQO1), and these antioxidative enzymes neutralize ROS. AHR/ARNT signaling also activates OVO-like 1 (OVOL1) transcription factor and upregulates the expression of filaggrin (FLG) and loricrin (LOR). AHR upregulates the expression of involucrin (IVL) in an OVOL1-independent manner. Therefore, AHR/ARNT signaling accelerates epidermal terminal differentiation and enhances the repair of barrier disruption. Interleukin (IL)-4 and IL-13 activate signal transducer and activator of transcription 6 (STAT6) and inhibit the OVOL1/FLG, OVOL1/LOR, and AHR/IVL axes. However, suitable AHR activation can inhibit the IL-4/IL-13-mediated STAT6 activation and restore the expression of FLG, LOR, and IVL. Regarding immune response, AHR signaling affects T-helper (Th17) differentiation and is essential for IL-22 production. AHR ligation (especially by high concentrations of ligands) induces the differentiation of regulatory cell populations, Treg and Tr1 cells. Tapinarof is an antioxidative AHR ligand and upregulates CYP1A1 expression. Topical tapinarof is efficacious in psoriasis and atopic dermatitis. Current studies demonstrate that tapinarof activates NRF2/antioxidative signaling and reduces oxidative stress. Tapinarof also upregulates FLG and IVL expression. Tapinarof downregulates IL-17A production and increases IL-22 production.
Figure 2
Figure 2
Human epidermal keratinocytes are stimulated with 10 ng/mL of IL-4 augments the protein expression of aryl hydrocarbon receptor (AHR) and AHR-nuclear translocator (ARNT) compared with untreated control by Western blot analysis.

References

    1. Furue K., Mitoma C., Tsuji G., Furue M. Protective role of peroxisome proliferator-activated receptor α agonists in skin barrier and inflammation. Immunobiology. 2018;223:327–330. doi: 10.1016/j.imbio.2017.10.047.
    1. Furue M., Fuyuno Y., Mitoma C., Uchi H., Tsuji G. Therapeutic agents with AHR inhibiting and NRF2 activating activity for managing chloracne. Antioxidants (Basel) 2018;7:90. doi: 10.3390/antiox7070090.
    1. Furue M., Hashimoto-Hachiya A., Tsuji G. Antioxidative phytochemicals accelerate epidermal terminal differentiation via the AHR-OVOL1 pathway: Implications for atopic dermatitis. Acta Derm. Venereol. 2018;98:918–923. doi: 10.2340/00015555-3003.
    1. Omiecinski C.J., Vanden Heuvel J.P., Perdew G.H., Peters J.M. Xenobiotic metabolism, disposition, and regulation by receptors: From biochemical phenomenon to predictors of major toxicities. Toxicol. Sci. 2011;120:S49–S75. doi: 10.1093/toxsci/kfq338.
    1. Esser C., Bargen I., Weighardt H., Haarmann-Stemmann T., Krutmann J. Functions of the aryl 1002 hydrocarbon receptor in the skin. Semin. Immunopathol. 2013;35:677–691. doi: 10.1007/s00281-013-0394-4.
    1. Furue M., Takahara M., Nakahara T., Uchi H. Role of AhR/ARNT system in skin homeostasis. Arch. Dermatol. Res. 2014;306:769–779. doi: 10.1007/s00403-014-1481-7.
    1. Mimura J., Fujii-Kuriyama Y. Functional role of AhR in the expression of toxic effects by TCDD. Biochim. Biophys. Acta. 2003;1619:263–268. doi: 10.1016/S0304-4165(02)00485-3.
    1. Fritsche E., Schäfer C., Calles C., Bernsmann T., Bernshausen T., Wurm M., Hübenthal U., Cline J.E., Hajimiragha H., Schroeder P., et al. Lightening up the UV response by identification of the aryl hydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc. Natl. Acad. Sci. USA. 2007;104:8851–8856. doi: 10.1073/pnas.0701764104.
    1. Rannug A., Rannug U., Rosenkranz H.S., Winqvist L., Westerholm R., Agurell E., Grafström A.K. Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. J. Biol. Chem. 1987;262:15422–15427.
    1. Furue M., Uchi H., Mitoma C., Hashimoto-Hachiya A., Chiba T., Ito T., Nakahara T., Tsuji G. Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients. 2017;9:223. doi: 10.3390/nu9030223.
    1. Magiatis P., Pappas P., Gaitanis G., Mexia N., Melliou E., Galanou M., Vlachos C., Stathopoulou K., Skaltsounis A.L., Marselos M., et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J. Investig. Dermatol. 2013;133:2023–2030. doi: 10.1038/jid.2013.92.
    1. Takei K., Mitoma C., Hashimoto-Hachiya A., Takahara M., Tsuji G., Nakahara T., Furue M. Galactomyces fermentation filtrate prevents T helper 2-mediated reduction of filaggrin in an aryl hydrocarbon receptor-dependent manner. Clin. Exp. Dermatol. 2015;40:786–793. doi: 10.1111/ced.12635.
    1. Takei K., Hashimoto-Hachiya A., Takahara M., Tsuji G., Nakahara T., Furue M. Cynaropicrin attenuates UVB-induced oxidative stress via the AhR-Nrf2-Nqo1 pathway. Toxicol. Lett. 2015;234:74–80. doi: 10.1016/j.toxlet.2015.02.007.
    1. Takei K., Mitoma C., Hashimoto-Hachiya A., Uchi H., Takahara M., Tsuji G., Kido-Nakahara M., Nakahara T., Furue M. Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor. J. Dermatol. 2015;42:171–180. doi: 10.1111/1346-8138.12717.
    1. Van den Bogaard E.H., Bergboer J.G., Vonk-Bergers M., van Vlijmen-Willems I.M., Hato S.V., van der Valk P.G., Schröder J.M., Joosten I., Zeeuwen P.L., Schalkwijk J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Investig. 2013;123:917–927. doi: 10.1172/JCI65642.
    1. Simpson E.L., Bieber T., Guttman-Yassky E., Beck L.A., Blauvelt A., Cork M.J., Silverberg J.I., Deleuran M., Kataoka Y., Lacour J.P., et al. Two Phase 3 Trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 2016;375:2335–2348. doi: 10.1056/NEJMoa1610020.
    1. Furue M., Ulzii D., Vu Y.H., Tsuji G., Kido-Nakahara M., Nakahara T. Pathogenesis of atopic dermatitis: Current paradigm. Iran. J. Immunol. 2019;16:97–107.
    1. Furue K., Ito T., Furue M. Differential efficacy of biologic treatments targeting the TNF-α/IL-23/IL-17 axis in psoriasis and psoriatic arthritis. Cytokine. 2018;111:182–188. doi: 10.1016/j.cyto.2018.08.025.
    1. Furue K., Ito T., Tsuji G., Kadono T., Furue M. Psoriasis and the TNF/IL23/IL17 axis. G. Ital. Dermatol. Venereol. 2019;154:418–424. doi: 10.23736/S0392-0488.18.06202-8.
    1. Tsoi L.C., Rodriguez E., Degenhardt F., Baurecht H., Wehkamp U., Volks N., Szymczak S., Swindell W.R., Sarkar M.K., Raja K., et al. Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J. Investig. Dermatol. 2019;139:1480–1489. doi: 10.1016/j.jid.2018.12.018.
    1. Peppers J., Paller A.S., Maeda-Chubachi T., Wu S., Robbins K., Gallagher K., Kraus J.E. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 2019;80:89–98. doi: 10.1016/j.jaad.2018.06.047.
    1. Robbins K., Bissonnette R., Maeda-Chubachi T., Ye L., Peppers J., Gallagher K., Kraus J.E. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J. Am. Acad. Dermatol. 2019;80:714–721. doi: 10.1016/j.jaad.2018.10.037.
    1. Kazlauskas A., Sundström S., Poellinger L., Pongratz I. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol. Cell. Biol. 2001;21:2594–2607. doi: 10.1128/MCB.21.7.2594-2607.2001.
    1. Lees M.J., Peet D.J., Whitelaw M.L. Defining the role for XAP2 in stabilization of the dioxin receptor. J. Biol. Chem. 2003;278:35878–35888. doi: 10.1074/jbc.M302430200.
    1. Hayes J.D., McMahon M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett. 2001;174:103–113. doi: 10.1016/S0304-3835(01)00695-4.
    1. 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. 2005;280:20340–20348. doi: 10.1074/jbc.M412081200.
    1. Esser C., Rannug A. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol. Rev. 2015;67:259–279. doi: 10.1124/pr.114.009001.
    1. Esser C. The aryl hydrocarbon receptor in immunity: Tools and potential. Methods Mol. Biol. 2016;1371:239–257.
    1. Stockinger B., Di Meglio P., Gialitakis M., Duarte J.H. The aryl hydrocarbon receptor: Multitasking in the immune system. Annu. Rev. Immunol. 2014;32:403–432. doi: 10.1146/annurev-immunol-032713-120245.
    1. Kopf P.G., Walker M.K. 2,3,7,8-tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A. Toxicol. Appl. Pharmacol. 2010;245:91–99. doi: 10.1016/j.taap.2010.02.007.
    1. Denison M.S., Soshilov A.A., He G., DeGroot D.E., Zhao B. Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 2011;124:1–22. doi: 10.1093/toxsci/kfr218.
    1. Baron J.M., Höller D., Schiffer R., Frankenberg S., Neis M., Merk H.F., Jugert F.K. Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. J. Investig. Dermatol. 2001;116:541–548. doi: 10.1046/j.1523-1747.2001.01298.x.
    1. Inui H., Itoh T., Yamamoto K., Ikushiro S., Sakaki T. Mammalian cytochrome P450-dependent metabolism of polychlorinated dibenzo-p-dioxins and coplanar polychlorinated biphenyls. Int. J. Mol. Sci. 2014;15:14044–14057. doi: 10.3390/ijms150814044.
    1. Anandasadagopan S.K., Singh N.M., Raza H., Bansal S., Selvaraj V., Singh S., Chowdhury A.R., Leu N.A., Avadhani N.G. β-Naphthoflavone-induced mitochondrial respiratory damage in Cyp1 knockout mouse and in cell culture systems: Attenuation by resveratrol treatment. Oxid. Med. Cell Longev. 2017;2017:5213186. doi: 10.1155/2017/5213186.
    1. Tanaka Y., Uchi H., Hashimoto-Hachiya A., Furue M. Tryptophan photoproduct FICZ upregulates IL1A, IL1B, and IL6 expression via oxidative stress in keratinocytes. Oxid. Med. Cell. Longev. 2018;2018:9298052. doi: 10.1155/2018/9298052.
    1. Tsuji G., Takahara M., Uchi H., Takeuchi S., Mitoma C., Moroi Y., Furue M. An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J. Dermatol. Sci. 2011;62:42–49. doi: 10.1016/j.jdermsci.2010.10.017.
    1. Nakahara T., Mitoma C., Hashimoto-Hachiya A., Takahara M., Tsuji G., Uchi H., Yan X., Hachisuka J., Chiba T., Esaki H., et al. Antioxidant Opuntia ficus-indica extract activates AHR-NRF2 signaling and upregulates filaggrin and loricrin expression in human keratinocytes. J. Med. Food. 2015;18:1143–1149. doi: 10.1089/jmf.2014.3396.
    1. Doi K., Mitoma C., Nakahara T., Uchi H., Hashimoto-Hachiya A., Takahara M., Tsuji G., Nakahara M., Furue M. Antioxidant Houttuynia cordata extract upregulates filaggrin expression in an aryl hydrocarbon-dependent manner. Fukuoka Igaku Zasshi. 2014;105:205–213.
    1. Tsuji G., Takahara M., Uchi H., Matsuda T., Chiba T., Takeuchi S., Yasukawa F., Moroi Y., Furue M. Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: The basis of its anti-inflammatory effect. J. Investig. Dermatol. 2012;132:59–68. doi: 10.1038/jid.2011.194.
    1. Yeager R.L., Reisman S.A., Aleksunes L.M., Klaassen C.D. Introducing the “TCDD-inducible AhR-Nrf2 gene battery”. Toxicol. Sci. 2009;111:238–246. doi: 10.1093/toxsci/kfp115.
    1. Wang K., Lv Q., Miao Y.M., Qiao S.M., Dai Y., Wei Z.F. Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway. Biochem. Pharmacol. 2018;155:494–509. doi: 10.1016/j.bcp.2018.07.039.
    1. Ma Q., Kinneer K., Bi Y., Chan J.Y., Kan Y.W. Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap ‘n’ collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): Cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem. J. 2004;377:205–213.
    1. Noda S., Harada N., Hida A., Fujii-Kuriyama Y., Motohashi H., Yamamoto M. Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse. Biochem. Biophys. Res. Commun. 2003;303:105–111. doi: 10.1016/S0006-291X(03)00306-1.
    1. Furue M., Tsuji G., Mitoma C., Nakahara T., Chiba T., Morino-Koga S., Uchi H. Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor. J. Dermatol. Sci. 2015;80:83–88. doi: 10.1016/j.jdermsci.2015.07.011.
    1. Kypriotou M., Huber M., Hohl D. The human epidermal differentiation complex: Cornified envelope precursors, S100 proteins and the ‘fused genes’ family. Exp. Dermatol. 2012;21:643–649. doi: 10.1111/j.1600-0625.2012.01472.x.
    1. Loertscher J.A., Lin T.M., Peterson R.E., Allen-Hoffmann B.L. In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin causes accelerated terminal differentiation in fetal mouse skin. Toxicol. Sci. 2002;68:465–472. doi: 10.1093/toxsci/68.2.465.
    1. Kennedy L.H., Sutter C.H., Leon Carrion S., Tran Q.T., Bodreddigari S., Kensicki E., Mohney R.P., Sutter T.R. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol. Sci. 2013;132:235–249. doi: 10.1093/toxsci/kfs325.
    1. Sutter C.H., Bodreddigari S., Campion C., Wible R.S., Sutter T.R. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation. Toxicol. Sci. 2011;124:128–137. doi: 10.1093/toxsci/kfr205.
    1. Fernandez-Salguero P.M., Ward J.M., Sundberg J.P., Gonzalez F.J. Lesions of aryl-hydrocarbon receptor-deficient mice. Vet. Pathol. 1997;34:605–614. doi: 10.1177/030098589703400609.
    1. Tauchi M., Hida A., Negishi T., Katsuoka F., Noda S., Mimura J., Hosoya T., Yanaka A., Aburatani H., Fujii-Kuriyama Y., et al. Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. Mol. Cell. Biol. 2005;25:9360–9368. doi: 10.1128/MCB.25.21.9360-9368.2005.
    1. Geng S., Mezentsev A., Kalachikov S., Raith K., Roop D.R., Panteleyev A.A. Targeted ablation of Arnt in mouse epidermis results in profound defects in desquamation and epidermal barrier function. J. Cell Sci. 2006;119:4901–4912. doi: 10.1242/jcs.03282.
    1. Takagi S., Tojo H., Tomita S., Sano S., Itami S., Hara M., Inoue S., Horie K., Kondoh G., Hosokawa K., et al. Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function. J. Clin. Investig. 2003;112:1372–1382. doi: 10.1172/JCI200318513.
    1. Ju Q., Fimmel S., Hinz N., Stahlmann R., Xia L., Zouboulis C.C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro. Exp. Dermatol. 2011;20:320–325. doi: 10.1111/j.1600-0625.2010.01204.x.
    1. Lin Y.K., Leu Y.L., Yang S.H., Chen H.W., Wang C.T., Pang J.H. Anti-psoriatic effects of indigo naturalis on the proliferation and differentiation of keratinocytes with indirubin as the active component. J. Dermatol. Sci. 2009;54:168–174. doi: 10.1016/j.jdermsci.2009.02.007.
    1. 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;48:555–574. doi: 10.1080/10408444.2018.1493086.
    1. Wincent E., Amini N., Luecke S., Glatt H., Bergman J., Crescenzi C., Rannug A., Rannug U. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 2009;284:2690–2696. doi: 10.1074/jbc.M808321200.
    1. Furue M., Uchi H., Mitoma C., Hashimoto-Hachiya A., Tanaka Y., Ito T., Tsuji G. Implications of tryptophan photoproduct FICZ in oxidative stress and terminal differentiation of keratinocytes. G. Ital. Dermatol. Venereol. 2019;154:37–41. doi: 10.23736/S0392-0488.18.06132-1.
    1. Kiyomatsu-Oda M., Uchi H., Morino-Koga S., Furue M. Protective role of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for arylhydrocarbon receptor, in chronic mite-induced dermatitis. J. Dermatol. Sci. 2018;90:284–294. doi: 10.1016/j.jdermsci.2018.02.014.
    1. Tsuji G., Ito T., Chiba T., Mitoma C., Nakahara T., Uchi H., Furue M. The role of the OVOL1-OVOL2 axis in normal and diseased human skin. J. Dermatol. Sci. 2018;90:227–231. doi: 10.1016/j.jdermsci.2018.02.005.
    1. Hong S.P., Kim M.J., Jung M.Y., Jeon H., Goo J., Ahn S.K., Lee S.H., Elias P.M., Choi E.H. Biopositive effects of low-dose UVB on epidermis: Coordinate upregulation of antimicrobial peptides and permeability barrier reinforcement. J. Investig. Dermatol. 2008;128:2880–2887. doi: 10.1038/jid.2008.169.
    1. Tsuji G., Hashimoto-Hachiya A., Kiyomatsu-Oda M., Takemura M., Ohno F., Ito T., Morino-Koga S., Mitoma C., Nakahara T., Uchi H., et al. Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis. Cell Death Dis. 2017;8:e2931. doi: 10.1038/cddis.2017.322.
    1. Hirano A., Goto M., Mitsui T., Hashimoto-Hachiya A., Tsuji G., Furue M. Antioxidant Artemisia princeps extract enhances the expression of filaggrin and loricrin via the AHR/OVOL1 pathway. Int. J. Mol. Sci. 2017;18:1948. doi: 10.3390/ijms18091948.
    1. Hashimoto-Hachiya A., Tsuji G., Murai M., Yan X., Furue M. Upregulation of FLG, LOR, and IVL expression by Rhodiola crenulata root extract via aryl hydrocarbon receptor: Differential involvement of OVOL. Int. J. Mol. Sci. 2018;19:1654. doi: 10.3390/ijms19061654.
    1. Van den Bogaard E.H., Podolsky M.A., Smits J.P., Cui X., John C., Gowda K., Desai D., Amin S.G., Schalkwijk J., Perdew G.H., et al. Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation. J. Investig. Dermatol. 2015;135:1320–1328. doi: 10.1038/jid.2015.6.
    1. Zhang W., Sakai T., Matsuda-Hirose H., Goto M., Yamate T., Hatano Y. Cutaneous permeability barrier function in signal transducer and activator of transcription 6-deficient mice is superior to that in wild-type mice. J. Dermatol. Sci. 2018;92:54–61. doi: 10.1016/j.jdermsci.2018.07.008.
    1. Tanaka G., Kanaji S., Hirano A., Arima K., Shinagawa A., Goda C., Yasunaga S., Ikizawa K., Yanagihara Y., Kubo M., et al. Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells. Int. Immunol. 2005;17:797–805. doi: 10.1093/intimm/dxh260.
    1. Mitamura Y., Nunomura S., Nanri Y., Ogawa M., Yoshihara T., Masuoka M., Tsuji G., Nakahara T., Hashimoto-Hachiya A., Conway S.J., et al. The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation. Allergy. 2018;73:1881–1891. doi: 10.1111/all.13437.
    1. Takemura M., Nakahara T., Hashimoto-Hachiya A., Furue M., Tsuji G. Glyteer, soybean tar, impairs IL-4/Stat6 signaling in murine bone marrow-derived dendritic cells: The basis of its therapeutic effect on atopic dermatitis. Int. J. Mol. Sci. 2018;19:1169. doi: 10.3390/ijms19041169.
    1. Schiering C., Vonk A., Das S., Stockinger B., Wincent E. Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem. Pharmacol. 2018;151:47–58. doi: 10.1016/j.bcp.2018.02.031.
    1. Ye J., Qiu J., Bostick J.W., Ueda A., Schjerven H., Li S., Jobin C., Chen Z.E., Zhou L. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Rep. 2017;21:2277–2290. doi: 10.1016/j.celrep.2017.10.114.
    1. Kiss E.A., Vonarbourg C., Kopfmann S., Hobeika E., Finke D., Esser C., Diefenbach A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011;334:1561–1565. doi: 10.1126/science.1214914.
    1. Lee J.S., Cella M., McDonald K.G., Garlanda C., Kennedy G.D., Nukaya M., Mantovani A., Kopan R., Bradfield C.A., Newberry R.D., et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 2011;13:144–151. doi: 10.1038/ni.2187.
    1. Qiu J., Heller J.J., Guo X., Chen Z.M., Fish K., Fu Y.X., Zhou L. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012;36:92–104. doi: 10.1016/j.immuni.2011.11.011.
    1. Liu J.Z., van Sommeren S., Huang H., Ng S.C., Alberts R., Takahashi A., Ripke S., Lee J.C., Jostins L., Shah T., et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 2015;47:979–986. doi: 10.1038/ng.3359.
    1. Monteleone I., Rizzo A., Sarra M., Sica G., Sileri P., Biancone L., MacDonald T.T., Pallone F., Monteleone G. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology. 2011;141:237–248. doi: 10.1053/j.gastro.2011.04.007.
    1. Schiering C., Wincent E., Metidji A., Iseppon A., Li Y., Potocnik A.J., Omenetti S., Henderson C.J., Wolf C.R., Nebert D.W., et al. Feedback control of AHR signalling regulates intestinal immunity. Nature. 2017;542:242–245. doi: 10.1038/nature21080.
    1. Holsapple M.P., Morris D.L., Wood S.C., Snyder N.K. 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced changes in immunocompetence: Possible mechanisms. Annu. Rev. Pharmacol. Toxicol. 1991;31:73–100. doi: 10.1146/annurev.pa.31.040191.000445.
    1. Veldhoen M., Hirota K., Westendorf A.M., Buer J., Dumoutier L., Renauld J.C., Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453:106–109. doi: 10.1038/nature06881.
    1. Funatake C.J., Marshall N.B., Steppan L.B., Mourich D.V., Kerkvliet N.I. 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. doi: 10.4049/jimmunol.175.7.4184.
    1. Qiu J., Guo X., Chen Z.M., He L., Sonnenberg G.F., Artis D., Fu Y.X., Zhou L. 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. doi: 10.1016/j.immuni.2013.08.002.
    1. Ehrlich A.K., Pennington J.M., Bisson W.H., Kolluri S.K., Kerkvliet N.I. TCDD, FICZ, and other high affinity AhR ligands dose-dependently determine the fate of CD4+ T cell differentiation. Toxicol. Sci. 2018;161:310–320. doi: 10.1093/toxsci/kfx215.
    1. Furue M., Chiba T., Tsuji G., Ulzii D., Kido-Nakahara M., Nakahara T., Kadono T. Atopic dermatitis: Immune deviation, barrier dysfunction, IgE autoreactivity and new therapies. Allergol. Int. 2017;66:398–403. doi: 10.1016/j.alit.2016.12.002.
    1. Seo E., Yoon J., Jung S., Lee J., Lee B.H., Yu J. Phenotypes of atopic dermatitis identified by cluster analysis in early childhood. J. Dermatol. 2019;46:117–123. doi: 10.1111/1346-8138.14714.
    1. Arima K., Gupta S., Gadkari A., Hiragun T., Kono T., Katayama I., Demiya S., Eckert L. Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey. J. Dermatol. 2018;45:390–396. doi: 10.1111/1346-8138.14218.
    1. Igarashi A., Fujita H., Arima K., Inoue T., Dorey J., Fukushima A., Taguchi Y. Health-care resource use and current treatment of adult atopic dermatitis patients in Japan: A retrospective claims database analysis. J. Dermatol. 2019;46:652–661. doi: 10.1111/1346-8138.14947.
    1. Jung H.J., Bae J.Y., Kim J.E., Na C.H., Park G.H., Bae Y.I., Shin M.K., Lee Y.B., Lee U.H., Jang Y.H., et al. Survey of disease awareness, treatment behavior and treatment satisfaction in patients with atopic dermatitis in Korea: A multicenter study. J. Dermatol. 2018;45:1172–1180. doi: 10.1111/1346-8138.14540.
    1. Komura Y., Kogure T., Kawahara K., Yokozeki H. Economic assessment of actual prescription of drugs for treatment of atopic dermatitis: Differences between dermatology and pediatrics in large-scale receipt data. J. Dermatol. 2018;45:165–174. doi: 10.1111/1346-8138.14133.
    1. Takeuchi S., Oba J., Esaki H., Furue M. Non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis. J. Dermatol. 2018;45:158–164. doi: 10.1111/1346-8138.14124.
    1. Williams H., Stewart A., von Mutius E., Cookson W., Anderson H.R. Is eczema really on the increase worldwide? J. Allergy Clin. Immunol. 2008;121:947–954. doi: 10.1016/j.jaci.2007.11.004.
    1. Furue M., Iida K., Imaji M., Nakahara T. Microbiome analysis of forehead skin in patients with atopic dermatitis and healthy subjects: Implication of Staphylococcus and Corynebacterium. J. Dermatol. 2018;45:876–877. doi: 10.1111/1346-8138.14486.
    1. Iwamoto K., Moriwaki M., Miyake R., Hide M. Staphylococcus aureus in atopic dermatitis: Strain-specific cell wall proteins and skin immunity. Allergol. Int. 2019;68:309–315. doi: 10.1016/j.alit.2019.02.006.
    1. Furue M., Kadono T. “Inflammatory skin march” in atopic dermatitis and psoriasis. Inflamm. Res. 2017;66:833–842. doi: 10.1007/s00011-017-1065-z.
    1. Li Z.Z., Zhong W.L., Hu H., Chen X.F., Zhang W., Huang H.Y., Yu B., Dou X. Aryl hydrocarbon receptor polymorphisms are associated with dry skin phenotypes in Chinese patients with atopic dermatitis. Clin. Exp. Dermatol. 2019;44:613–619. doi: 10.1111/ced.13841.
    1. Li D., Takao T., Tsunematsu R., Morokuma S., Fukushima K., Kobayashi H., Saito T., Furue M., Wake N., Asanoma K. Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer. Oncogene. 2013;32:4950–4959. doi: 10.1038/onc.2012.509.
    1. Liu G., Asanoma K., Takao T., Tsukimori K., Uchi H., Furue M., Kato K., Wake N. Aryl hydrocarbon receptor SNP -130 C/T associates with dioxins susceptibility through regulating its receptor activity and downstream effectors including interleukin. Toxicol. Lett. 2015;232:384–392. doi: 10.1016/j.toxlet.2014.11.025.
    1. Hong C.H., Lee C.H., Yu H.S., Huang S.K. Benzopyrene, a major polyaromatic hydrocarbon in smoke fume, mobilizes Langerhans cells and polarizes Th2/17 responses in epicutaneous protein sensitization through the aryl hydrocarbon receptor. Int. Immunopharmacol. 2016;36:111–117. doi: 10.1016/j.intimp.2016.04.017.
    1. Kim H.O., Kim J.H., Chung B.Y., Choi M.G., Park C.W. Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases. Exp. Dermatol. 2014;23:278–281. doi: 10.1111/exd.12350.
    1. Yu J., Luo Y., Zhu Z., Zhou Y., Sun L., Gao J., Sun J., Wang G., Yao X., Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor. J. Allergy Clin. Immunol. 2019;143:2108–2119. doi: 10.1016/j.jaci.2018.11.036.
    1. Hidaka T., Ogawa E., Kobayashi E.H., Suzuki T., Funayama R., Nagashima T., Fujimura T., Aiba S., Nakayama K., Okuyama R., et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nat. Immunol. 2017;18:64–73. doi: 10.1038/ni.3614.
    1. Bissonnette R., Poulin Y., Zhou Y., Tan J., Hong H.C., Webster J., Ip W., Tang L., Lyle M. Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: Results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial. Br. J. Dermatol. 2012;166:853–860. doi: 10.1111/j.1365-2133.2011.10775.x.
    1. Richardson W.H., Schmidt T.M., Nealson K.H. Identification of an anthraquinone pigment and a hydroxystilbene antibiotic from Xenorhabdus luminescens. Appl. Environ. Microbiol. 1988;54:1602–16055.
    1. Smith S.H., Jayawickreme C., Rickard D.J., Nicodeme E., Bui T., Simmons C., Coquery C.M., Neil J., Pryor W.M., Mayhew D., et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J. Investig. Dermatol. 2017;137:2110–2119. doi: 10.1016/j.jid.2017.05.004.
    1. Zang Y.N., Jiang D.L., Cai L., Chen X., Wang Q., Xie Z.W., Liu Y., Zhang C.Y., Jing S., Chen G.H., et al. Use of a dose-response model to guide future clinical trial of Benvitimod cream to treat mild and moderate psoriasis. Int. J. Clin. Pharmacol. Ther. 2016;54:87–95. doi: 10.5414/CP202486.
    1. Bissonnette R., Vasist L.S., Bullman J.N., Collingwood T., Chen G., Maeda-Chubachi T. Systemic pharmacokinetics, safety, and preliminary efficacy of topical AhR agonist Tapinarof: Results of a phase 1 study. Clin. Pharmacol. Drug Dev. 2018;7:524–531. doi: 10.1002/cpdd.439.
    1. Miake S., Tsuji G., Takemura M., Hashimoto-Hachiya A., Vu Y.H., Furue M., Nakahara T. IL-4 augments IL-31/IL-31 receptor alpha interaction leading to enhanced Ccl17 and Ccl22 production in dendritic cells: Implications for atopic dermatitis. Int. J. Mol. Sci. 2019;20:4053. doi: 10.3390/ijms20164053.
    1. Koch S., Stroisch T.J., Vorac J., Herrmann N., Leib N., Schnautz S., Kirins H., Forster I., Weighardt H., Bieber T. AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO. Allergy. 2017;72:1686–1693. doi: 10.1111/all.13170.
    1. Edamitsu T., Taguchi K., Kobayashi E.H., Okuyama R., Yamamoto M. Aryl hydrocarbon receptor directly regulates artemin gene expression. Mol. Cell Biol. 2019;39 doi: 10.1128/MCB.00190-19.
    1. Morita A. Current developments in phototherapy for psoriasis. J. Dermatol. 2018;45:287–292. doi: 10.1111/1346-8138.14213.
    1. Ortiz-Salvador J.M., Pérez-Ferriols A. Phototherapy in Atopic Dermatitis. Adv. Exp. Med. Biol. 2017;996:279–286.
    1. Boehncke W.H., Schön M.P. Psoriasis. Lancet. 2015;386:983–994. doi: 10.1016/S0140-6736(14)61909-7.
    1. Furue M., Kadono T. The contribution of IL-17 to the development of autoimmunity in psoriasis. Innate Immun. 2019;25:337–343. doi: 10.1177/1753425919852156.
    1. Ogawa E., Okuyama R., Seki T., Kobayashi A., Oiso N., Muto M., Nakagawa H., Kawada A. Epidemiological survey of patients with psoriasis in Matsumoto city, Nagano Prefecture, Japan. J. Dermatol. 2018;45:314–317. doi: 10.1111/1346-8138.14101.
    1. Ito T., Takahashi H., Kawada A., Iizuka H., Nakagawa H. Epidemiological survey from 2009 to 2012 of psoriatic patients in Japanese Society for Psoriasis Research. J. Dermatol. 2018;45:293–301. doi: 10.1111/1346-8138.14105.
    1. Ichiyama S., Ito M., Funasaka Y., Abe M., Nishida E., Muramatsu S., Nishihara H., Kato H., Morita A., Imafuku S., et al. Assessment of medication adherence and treatment satisfaction in Japanese patients with psoriasis of various severities. J. Dermatol. 2018;45:727–731. doi: 10.1111/1346-8138.14225.
    1. Takahashi H., Satoh K., Takagi A., Iizuka H. Cost-efficacy and pharmacoeconomics of psoriatic patients in Japan: Analysis from a single outpatient clinic. J. Dermatol. 2019;46:478–481. doi: 10.1111/1346-8138.14876.
    1. Komatsu-Fujii T., Honda T., Otsuka A., Kabashima K. Improvement of nail lesions in a patient with psoriatic arthritis by switching the treatment from an anti-interleukin-17A antibody to an anti-tumor necrosis factor-α antibody. J. Dermatol. 2019;46:e158–e160. doi: 10.1111/1346-8138.14700.
    1. Tsuruta N., Narisawa Y., Imafuku S., Ito K., Yamaguchi K., Miyagi T., Takahashi K., Fukamatsu H., Morizane S., Koketsu H., et al. Cross-sectional multicenter observational study of psoriatic arthritis in Japanese patients: Relationship between skin and joint symptoms and results of treatment with tumor necrosis factor-α inhibitors. J. Dermatol. 2019;46:193–198. doi: 10.1111/1346-8138.14745.
    1. Yamamoto T., Ohtsuki M., Sano S., Morita A., Igarashi A., Okuyama R., Kawada A. Late-onset psoriatic arthritis in Japanese patients. J. Dermatol. 2019;46:169–170. doi: 10.1111/1346-8138.14752.
    1. Chujo S., Asahina A., Itoh Y., Kobayashi K., Sueki H., Ishiji T., Umezawa Y., Nakagawa H. New onset of psoriasis during nivolumab treatment for lung cancer. J. Dermatol. 2018;45:e55–e56. doi: 10.1111/1346-8138.14167.
    1. Furue K., Ito T., Tsuji G., Kadono T., Nakahara T., Furue M. Autoimmunity and autoimmune co-morbidities in psoriasis. Immunology. 2018;154:21–27. doi: 10.1111/imm.12891.
    1. Ho Y.H., Hu H.Y., Chang Y.T., Li C.P., Wu C.Y. Psoriasis is associated with increased risk of bullous pemphigoid: A nationwide population-based cohort study in Taiwan. J. Dermatol. 2019;46:604–609. doi: 10.1111/1346-8138.14902.
    1. Ichiyama S., Hoashi T., Kanda N., Hashimoto H., Matsushita M., Nozawa K., Ueno T., Saeki H. Psoriasis vulgaris associated with systemic lupus erythematosus successfully treated with apremilast. J. Dermatol. 2019;46:e219–e221. doi: 10.1111/1346-8138.14728.
    1. Kamata M., Asano Y., Shida R., Maeda N., Yoshizaki A., Miyagaki T., Kawashima T., Tada Y., Sato S. Secukinumab decreased circulating anti-BP180-NC16a autoantibodies in a patient with coexisting psoriasis vulgaris and bullous pemphigoid. J. Dermatol. 2019;46:e216–e217. doi: 10.1111/1346-8138.14760.
    1. Masaki S., Bayaraa B., Imafuku S. Prevalence of inflammatory bowel disease in Japanese psoriatic patients. J. Dermatol. 2019;46:590–594. doi: 10.1111/1346-8138.14900.
    1. Chiu H.Y., Chang W.L., Shiu M.N., Huang W.F., Tsai T.F. Psoriasis is associated with a greater risk for cardiovascular procedure and surgery in patients with hypertension: A nationwide cohort study. J. Dermatol. 2018;45:1381–1388. doi: 10.1111/1346-8138.14654.
    1. Momose M., Asahina A., Fukuda T., Sakuma T., Umezawa Y., Nakagawa H. Evaluation of epicardial adipose tissue volume and coronary artery calcification in Japanese patients with psoriasis vulgaris. J. Dermatol. 2018;45:1349–1352. doi: 10.1111/1346-8138.14618.
    1. Takamura S., Takahashi A., Inoue Y., Teraki Y. Effects of tumor necrosis factor-α, interleukin-23 and interleukin-17A inhibitors on bodyweight and body mass index in patients with psoriasis. J. Dermatol. 2018;45:1130–1134. doi: 10.1111/1346-8138.14526.
    1. Han J.H., Lee J.H., Han K.D., Kim H.N., Bang C.H., Park Y.M., Lee J.Y., Kim T.Y. Increased risk of psoriasis in subjects with abdominal obesity: A nationwide population-based study. J. Dermatol. 2019;46:695–701. doi: 10.1111/1346-8138.14939.
    1. Yamazaki F., Takehana K., Tamashima M., Okamoto H. Improvement in abnormal coronary arteries estimated by coronary computed tomography angiography after secukinumab treatment in a Japanese psoriatic patient. J. Dermatol. 2019;46:e51–e52. doi: 10.1111/1346-8138.14545.
    1. Bayaraa B., Imafuku S. Sustainability and switching of biologics for psoriasis and psoriatic arthritis at Fukuoka University Psoriasis Registry. J. Dermatol. 2019;46:389–398. doi: 10.1111/1346-8138.14834.
    1. Nakajima K., Sano S. Mouse models of psoriasis and their relevance. J. Dermatol. 2018;45:252–263. doi: 10.1111/1346-8138.14112.
    1. Ogawa E., Sato Y., Minagawa A., Okuyama R. Pathogenesis of psoriasis and development of treatment. J. Dermatol. 2018;45:264–272. doi: 10.1111/1346-8138.14139.
    1. Kamata M., Tada Y. Safety of biologics in psoriasis. J. Dermatol. 2018;45:279–286. doi: 10.1111/1346-8138.14096.
    1. Tada Y., Ishii K., Kimura J., Hanada K., Kawaguchi I. Patient preference for biologic treatments of psoriasis in Japan. J. Dermatol. 2019;46:466–477. doi: 10.1111/1346-8138.14870.
    1. Bayaraa B., Imafuku S. Relationship between environmental factors, age of onset and familial history in Japanese patients with psoriasis. J. Dermatol. 2018;45:715–718. doi: 10.1111/1346-8138.14321.
    1. Elder J.T. Expanded genome-wide association study meta-analysis of psoriasis expands the catalog of common psoriasis-associated variants. J. Investig. Dermatol. Symp. Proc. 2018;19:S77–S78. doi: 10.1016/j.jisp.2018.09.005.
    1. Di Meglio P., Duarte J.H., Ahlfors H., Owens N.D., Li Y., Villanova F., Tosi I., Hirota K., Nestle F.O., Mrowietz U., et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity. 2014;40:989–1001. doi: 10.1016/j.immuni.2014.04.019.
    1. Smith S.H., Peredo C.E., Takeda Y., Bui T., Neil J., Rickard D., Millerman E., Therrien J.P., Nicodeme E., Brusq J.M., et al. Development of a topical treatment for psoriasis targeting RORγ: From bench to skin. PLoS ONE. 2016;11:e0147979. doi: 10.1371/journal.pone.0147979.
    1. Cochez P.M., Michiels C., Hendrickx E., Van Belle A.B., Lemaire M.M., Dauguet N., Warnier G., de Heusch M., Togbe D., Ryffel B., et al. AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model. Eur. J. Immunol. 2016;46:1449–1459. doi: 10.1002/eji.201546070.
    1. Mescher M., Tigges J., Rolfes K.M., Shen A.L., Yee J.S., Vogeley C., Krutmann J., Bradfield C.A., Lang D., Haarmann-Stemmann T. The Toll-like receptor agonist imiquimod is metabolized by aryl hydrocarbon receptor-regulated cytochrome P450 enzymes in human keratinocytes and mouse liver. Arch. Toxicol. 2019;93:1917–1926. doi: 10.1007/s00204-019-02488-5.
    1. Beranek M., Fiala Z., Kremlacek J., Andrys C., Krejsek J., Hamakova K., Palicka V., Borska L. Serum levels of aryl hydrocarbon receptor, cytochromes P450 1A1 and 1B1 in patients with exacerbated psoriasis vulgaris. Folia Biol. (Praha) 2018;64:97–102.
    1. Bissonnette R., Bolduc C., Maari C., Nigen S., Webster J.M., Tang L., Lyle M. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: Results from a randomized double-blind placebo-controlled, phase II trial. J. Eur. Acad. Dermatol. Venereol. 2012;26:1516–1521. doi: 10.1111/j.1468-3083.2011.04332.x.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa