The pathogenesis of psoriasis is complex. Aryl hydrocarbon receptor (AhR) is a transcription factor that can be bound and activated by structurally diverse ligands and plays an important role in a range of biological processes and in the pathogenesis of different diseases. Recently, the role of AhR in psoriasis has attracted attention. AhR has toxicological functions and physiological functions. The overexpression and activation of AhR induced by the environmental pollutant and exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can drive the development of psoriasis. This TCDD-mediated toxicological response disrupts the physiological functions of AhR resulting in skin barrier disorders and the release of inflammatory cytokines, 2 of the pivotal factors of psoriasis. In addition, highly upregulated kynureninase in psoriasis decreases endogenous AhR agonists, thereby weakening the physiological functions of AhR. Activating AhR physiological signalling should be useful in the treatment of psoriasis. Studies have demonstrated that physiological activation of AhR can dampen the severity of psoriasis. The oldest and effective treatment for psoriasis coal tar works by activating AhR, and both new anti-psoriasis drugs tapinarof and benvitimod are formulations of AhR agonist, supporting that activation of AhR can be used as a new strategy for the treatment of psoriasis. Preclinical and preliminary clinical studies have revealed the anti-psoriasis effects of a number of AhR agonists, providing potential candidates for the development of new drugs for the treatment of psoriasis.
OrsmondABereza-MalcolmLLynchTMarchLXueM. Skin barrier dysregulation in psoriasis. Int J Mol Sci. 2021;22(19):10841. doi:10.3390/ijms221910841
2.
NapolitanoMFabbrociniGMartoraFPiconeVMorelliPPatrunoC.Role of aryl hydrocarbon receptor activation in inflammatory chronic skin diseases. Cells. 2021;10(12):3559. doi:10.3390/cells10123559
3.
BissonnetteRGoldLSRubensteinDSTallmanAMArmstrongA.Tapinarof in the treatment of psoriasis: a review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent. J Am Acad Dermatol. 2021;84(4):1059-1067. doi:10.1016/j.jaad.2020.10.085
4.
KouZDaiW.Aryl hydrocarbon receptor: its roles in physiology. Biochem Pharmacol. 2021;185:114428. doi:10.1016/j.bcp.2021.114428
5.
SoshilovAADenisonMS.Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol. 2014;34(9):1707-1719. doi:10.1128/MCB.01183-13
6.
MahioutSTagliabueSGNasriA, et al. In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators. Toxicol In Vitro. 2018;52:178-188. doi:10.1016/j.tiv.2018.06.010
7.
ShermehASRoyzmanDKuhntC.Differential modulation of dendritic cell biology by endogenous and exogenous aryl hydrocarbon receptor ligands. Int J Mol Sci. 2023;24(9):7801. doi:10.3390/ijms24097801
8.
SchieringCWincentEMetidjiA, et al. Feedback control of AHR signalling regulates intestinal immunity. Nature. 2017;542(7640):242-245. doi:10.1038/nature21080
9.
MimuraJEmaMSogawaKFujii-KuriyamaY.Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev. 1999;13(1):20-25. doi:10.1101/gad.13.1.20
10.
RomanÁCCarvajal-GonzalezJMMerinoJMMulero-NavarroSFernández-SalgueroPM. The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. Pharmacol Ther. 2018;185:50-63. doi:10.1016/j.pharmthera.2017.12.003
11.
Gutiérrez-VázquezCQuintanaFJ.Regulation of the immune response by the aryl hydrocarbon receptor. Immunity. 2018;48:19-33. doi:10.1016/j.immuni.2017.12.012
12.
LoertscherJASattlerCAAllen-HoffmannBL.2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the differentiation pattern of human keratinocytes in organotypic culture. Toxicol Appl Pharmacol. 2001;175:121-129. doi:10.1006/taap.2001.9202
13.
Di MeglioPDuarteJHAhlforsH, et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity. 2014;40(6):989-1001. doi:10.1016/j.immuni.2014.04.019
14.
KimHOKimJHChungBYChoiMGParkCW.Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases. Exp Dermatol. 2014;23(4):278-281. doi:10.1111/exd.12350
15.
KimHRKangSYKimHOParkCWChungBY.Role of aryl hydrocarbon receptor activation and autophagy in psoriasis-related inflammation. Int J Mol Sci. 2020;21(6):2195. doi:10.3390/ijms21062195
16.
KimJEKimHRKangSY, et al. Aryl hydrocarbon Receptor and autophagy-related protein microtubule-associated protein light chain 3 expression in psoriasis. Ann Dermatol. 2021;33(2):138-146. doi:10.5021/ad.2021.33.2.138
17.
UmJYKimHBKangSY, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin regulates the expression of aryl hydrocarbon receptor-related factors and cytokines in peripheral blood mononuclear cells and CD4+ T cells from patients with atopic dermatitis and psoriasis. Ann Dermatol. 2020;32(5):360-369. doi:10.5021/ad.2020.32.5.360
18.
BeránekMFialaZKremláčekJ, et al. Serum levels of aryl hydrocarbon receptor, cytochromes P450 1A1 and 1B1 in patients with exacerbated psoriasis vulgaris. Folia Biol (Praha). 2018;64(3):97-102.
19.
KaradagASUzunçakmakTKOzkanliS, et al. An investigation of cytochrome p450 (CYP) and glutathione S-transferase (GST) isoenzyme protein expression and related interactions with phototherapy in patients with psoriasis vulgaris. Int J Dermatol. 2017;56(2):225-231. doi:10.1111/ijd.13343
20.
KyorevaMLiYHoosenallyM, et al. CYP1A1 enzymatic activity influences skin inflammation via regulation of the AHR pathway. J Invest Dermatol. 2021;141:1553-1563.e3. doi:10.1016/j.jid.2020.11.024
21.
LuoODRidhaZJfriA, et al. Neighborhood characteristics and the risk of psoriasis: a systematic review. JAAD Int. 2023;13:100-101.
22.
BellinatoFAdamiGVaientiS, et al. Association between short-term exposure to environmental air pollution and psoriasis flare. JAMA Dermatol. 2022 ;158(4):375-381. doi:10.1001/jamadermatol.2021.6019
23.
ZhouHWuRKongYZhaoMSuY.Impact of smoking on psoriasis risk and treatment efficacy: a meta-analysis. J Int Med Res. 2020;48(10):300060520964024. doi:10.1177/0300060520964024
24.
MarshallNBKerkvlietNI.Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Ann N Y Acad Sci. 2010;1183:25-37. doi:10.1111/j.1749-6632.2009.05125.x
25.
MutoHTakizawaY.Dioxins in cigarette smoke. Arch Environ Health. 1989;44(3):171-174. doi:10.1080/00039896.1989.9935882
26.
EsserCBargenIWeighardtHHaarmann-StemmannTKrutmannJ.Functions of the aryl hydrocarbon receptor in the skin. Semin Immunopathol. 2013;35:677-691. doi:10.1007/s00281-013-0394-4
27.
PanteleyevAABickersDR.Dioxin-induced chloracne – Reconstructing the cellular and molecular mechanisms of a classic environmental disease. Exp Dermatol. 2006;15:705–730.
28.
BradySP.Parakeratosis. J Am Acad Dermatol. 2004;50:77-84. doi:10.1016/s0190-9622(03)02801-9
29.
KimHRKimJCKangSYKimHOParkCWChungBY.Rapamycin alleviates 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis by inducing autophagy. Int J Mol Sci. 2021;22(8):3968. doi:10.3390/ijms22083968
30.
BlagovASukhorukovVGuoSZhangDEreminIOrekhovA.The role of oxidative stress in the induction and development of psoriasis. Front Biosci (Landmark Ed). 2023;28:118. doi:10.31083/j.fbl2806118
31.
MorelYMermodNBaroukiR.An autoregulatory loop controlling CYP1A1 gene expression: role of H(2)O(2) and NFI. Mol Cell Biol. 1999;19:6825-6832.
32.
OgawaTIshitsukaYInoueS, et al. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates epidermal keratinization under psoriatic skin inflammation. Am J Pathol. 2020;190:577-585. doi:10.1016/j.ajpath.2019.10.022
33.
LeeHMShinDMYukJM, et al. Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J Immunol. 2011;186:1248-1258. doi:10.4049/jimmunol.1001954
34.
UmJYChungBYKimHBKimJCParkCWKimHO.Aryl hydrocarbon receptor repressor is hypomethylated in psoriasis and promotes psoriasis-like inflammation in HaCaT Cells. Int J Mol Sci. 2021;22:12715. doi:10.3390/ijms222312715
35.
Haarmann-StemmannTEsserCKrutmannJ.The Janus-faced role of aryl hydrocarbon receptor signaling in the skin: consequences for prevention and treatment of skin disorders. J Invest Dermatol. 2015;135(11):2572-2576. doi:10.1038/jid.2015.285
36.
MitchellKAElferinkCJ.Timing is everything: consequences of transient and sustained AhR activity. Biochem Pharmacol. 2009;77(6):947-56. doi:10.1016/j.bcp.2008.10.028
37.
BockKWKöhleC.Ah receptor: dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochem Pharmacol. 2006;72(4):393-404. doi:10.1016/j.bcp.2006.01.017
38.
Mulero-NavarroSFernandez-SalgueroPM.New trends in aryl hydrocarbon receptor biology. Front Cell Dev Biol. 2016;4:45. doi:10.3389/fcell.2016.00045
39.
Fernández-GallegoNSánchez-MadridFCibrianD.Role of AHR ligands in skin homeostasis and cutaneous inflammation. Cells. 2021;10:3176. doi:10.3390/cells10113176
40.
HardenJLLewisSMLishSR, et al. The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases. J Allergy Clin Immunol. 2016;137(6):1830-1840. doi:10.1016/j.jaci.2015.09.055
41.
GaoJXuKLiuH, et al. Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front Cell Infect Microbiol. 2018;8:13. doi:10.3389/fcimb.2018.00013
42.
van den BogaardEHBergboerJGVonk-BergersM, et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013;123(2):917-27. doi:10.1172/JCI65642
43.
GoldLSRubensteinDSPeistKJainPTallmanAM.Tapinarof cream 1% once daily and benvitimod 1% twice daily are 2 distinct topical medications. J Am Acad Dermatol. 2021;85(3):e201-e202. doi:10.1016/j.jaad.2021.04.103
44.
BissonnetteRChenGBolducCMaariC, et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2A, randomized, placebo-controlled clinical trial. Arch Dermatol. 2010;146(4):446-449. doi:10.1001/archdermatol.2010.34
45.
KeamSJ.Tapinarof Cream 1%: first Approval. Drugs. 2022;82(11):1221-1228. doi:10.1007/s40265-022-01748-6
46.
RobbinsKBissonnetteRMaeda-ChubachiT, et al. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J Am Acad Dermatol. 2019;80(3):714-721. doi:10.1016/j.jaad.2018.10.037
47.
LebwohlMGGoldLSStroberB, et al. Phase 3 trials of tapinarof cream for plaque psoriasis. N Engl J Med. 2021;385(24):2219-2229. doi:10.1056/NEJMoa2103629
48.
StroberBGoldLSBissonnetteR, et al. One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: results from the PSOARING 3 trial. J Am Acad Dermatol. 2022:87(4): 800-806. doi:10.1016/j.jaad.2022.06.1171
49.
CaiZZengYShiXZhangXZhuHWangW.Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway. J Dermatol Sci. 2023;109:71-79. doi:10.1016/j.jdermsci.2023.01.010
50.
BissonnetteRBolducCMaariC, et al. 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(12):1516-1521. doi:10.1111/j.1468-3083.2011.04332.x
51.
CaiLChenGHLuQJ, et al. A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis. Chin Med J (Engl). 2020;133(24):2905-2909. doi:10.1097/CM9.0000000000001221
52.
ZhangJCaiLZhengM.A novel topical treatment for plaque psoriasis: benvitimod/tapinarof. J Am Acad Dermatol. 2022;86(3):e137-e138. doi:10.1016/j.jaad.2021.10.053
53.
PhelanDWinterGMRogersWJLamJCDenisonMS.Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys. 1998;357(1):155-163. doi:10.1006/abbi.1998.0814
54.
KeumHKimTWKimY, et al. Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling. J Control Release. 2020;325:359-369. doi:10.1016/j.jconrel.2020.07.015
55.
MarinelliLMartin-GallausiauxCBourhisJMBéguet-CrespelFBlottièreHMLapaqueN.Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep. 2019;9(1):643. doi:10.1038/s41598-018-37019-2
56.
SchwarzAPhilippsenRSchwarzT.Induction of regulatory T cells and correction of cytokine disbalance by short-chain fatty acids: implications for psoriasis therapy. J Invest Dermatol. 2021;141(1):95-104.e2. doi:10.1016/j.jid.2020.04.031
57.
LiHJWuNLPuCMHsiaoCYChangDCHungCF.Chrysin alleviates imiquimod-induced psoriasis-like skin inflammation and reduces the release of CCL20 and antimicrobial peptides. Sci Rep. 2020;10(1):2932. doi:10.1038/s41598-020-60050-1
58.
ZhangSQinCSafeSH.Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003;111(16):1877-1882. doi:10.1289/ehp.6322
59.
RannugARannugU.The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation. Crit Rev Toxicol. 2018;48(7):555-574. doi:10.1080/10408444.2018.1493086
60.
HuQHeGZhaoJ, et al. Ginsenosides are novel naturally-occurring aryl hydrocarbon receptor ligands. PLoS One. 2013;8(6):e66258. doi:10.1371/journal.pone.0066258
BittingerMANguyenLPBradfieldCA.Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. Mol Pharmacol. 2003;64(3):550-556. doi:10.1124/mol.64.3.550
63.
YangHJYangTHSuCC.5-hydroxytryptophan attenuates imiquimod-induced psoriasiform dermatitis probably through inhibition of IL-17A production and keratinocyte activation. Exp Dermatol. 2018;27(11):1273-1279. doi:10.1111/exd.13781
64.
YangLLiXHuangWRaoXLaiY.Pharmacological properties of indirubin and its derivatives. Biomed Pharmacother. 2022;151:113112. doi:10.1016/j.biopha.2022.113112
65.
FaberSCSoshilovAAGiani TagliabueSBonatiLDenisonMS.Comparative in vitro and in silico analysis of the selectivity of indirubin as a human Ah receptor agonist. Int J Mol Sci. 2018;19(9):2692. doi:10.3390/ijms19092692
66.
XieXJDiTTWangY, et al. Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδ T cells. Mol Immunol. 2018;101:386-395. doi:10.1016/j.molimm.2018.07.011
67.
LinYKSeeLCHuangYHChiCCHuiRC.Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: a randomized, double-blind, dosage-controlled trial. Br J Dermatol. 2018;178(1):124-131. doi:10.1111/bjd.15894
68.
SchaldachCMRibyJBjeldanesLF.Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry. 1999;38(23):7594-7600. doi:10.1021/bi982861e
69.
HuFQuZChenK, et al. Lipoxin A4 Ameliorates imiquimod-induced psoriasis-like dermatitis via promoting the regression of inflammation. Clin Cosmet Investig Dermatol. 2023;16:2103-2111. doi:10.2147/CCID.S418467
70.
ChenHLuCLiuH, et al. Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway. Int Immunopharmacol. 2017;48:110-117. doi:10.1016/j.intimp.2017.04.022
71.
CiolinoHPDaschnerPJYehGC.Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem J. 1999;340(pt 3):715-722.
72.
VijayalakshmiARavichandiranVMalarkodiVNirmalaSJayakumariS.Screening of flavonoid “quercetin” from the rhizome of Smilax china Linn. for anti-psoriatic activity. Asian Pac J Trop Biomed. 2012;2(4):269-275. doi:10.1016/S2221-1691(12)60021-5
73.
PastorkováBVrzalováABachledaPDvořákZ.Hydroxystilbenes and methoxystilbenes activate human aryl hydrocarbon receptor and induce CYP1A genes in human hepatoma cells and human hepatocytes. Food Chem Toxicol. 2017;103:122-132. doi:10.1016/j.fct.2017.03.008
LiuYChenYZhuRXuLXieHQZhaoB.Rutaecarpine inhibits U87 glioblastoma cell migration by activating the aryl hydrocarbon receptor signaling pathway. Front Mol Neurosci. 2021;14:765712. doi:10.3389/fnmol.2021.765712
76.
LiYZhangGChenM, et al. Rutaecarpine inhibited imiquimod-induced psoriasis-like dermatitis via inhibiting the NF-κB and TLR7 pathways in mice. Biomed Pharmacother. 2019;109:1876-1883. doi:10.1016/j.biopha.2018.10.062
77.
CardinaliGFloriEMastrofrancescoA, et al. Anti-inflammatory and pro-differentiating properties of the aryl hydrocarbon receptor ligands NPD-0614-13 and NPD-0614-24: potential therapeutic benefits in psoriasis. Int J Mol Sci. 2021;22(14):7501. doi:10.3390/ijms22147501
78.
LiuJPiZXiaoY, et al. Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling. Pharmacol Res. 2022;176:106057. doi:10.1016/j.phrs.2022.106057
79.
BafuttoMOliveiraECZaterkaS.Evaluation of psoriasis treatment with esomeprazole – a pilot study. Arq Gastroenterol. 2019;56(3):261-263. doi:10.1590/S0004-2803.201900000-49
80.
O’DonnellEFSailiKSKochDC, et al. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One. 2010;5(10):e13128. doi:10.1371/journal.pone.0013128
81.
Tlacuilo-ParraJAGuevara-GutiérrezERodríguez-CastellanosMAOrnelas-AguirreJMBarba-GómezJFSalazar-PáramoM.Leflunomide in the treatment of psoriasis: results of a phase II open trial. Br J Dermatol. 2004;150(5):970-976. doi:10.1111/j.1365-2133.2004.05836.x
82.
NashPThaçiDBehrensFFalkFKaltwasserJP.Leflunomide improves psoriasis in patients with psoriatic arthritis: an in-depth analysis of data from the TOPAS study. Dermatology. 2006;212(3):238-249. doi:10.1159/000091251
83.
TianCZhangGXiaZChenNYangSLiL.Identification of triazolopyridine derivatives as a new class of AhR agonists and evaluation of anti-psoriasis effect in a mouse model. Eur J Med Chem. 2022;231:114122. doi:10.1016/j.ejmech.2022.114122
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
