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The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin

Abstract

Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

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Figure 1: The phenotype of AhR-CA mice recapitulates the pathology of human AD.
Figure 2: AhR-CA mice develop an enhanced asthmatic response to percutaneous sensitization with antigens.
Figure 3: Skin-barrier destruction by scratching enhances percutaneous sensitization in AhR-CA mice.
Figure 4: Scratching characterized by hypersensitivity to pruritus with epidermal hyper-innervation in AhR-CA mice.
Figure 5: AhR-induced expression of Artn elicits epidermal hyper-innervation and subsequent alloknesis.
Figure 6: Exposure to air pollutants recapitulates AD-like pathologies via AhR.
Figure 7: The AhR–artemin axis is activated in patients with AD and is induced by air pollutants.

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Acknowledgements

We thank K. Kuroda for bioinformatics support; M. Nakagawa, M. Kikuchi, M. Tsuda, S. Inomata, A. Gotoh and A. Uchiyama for technical assistance; the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support; J. Takeda (Osaka University) for Krt5-Cre mice; N. E. Fusenig (Deutsches Krebsforschungszentrum) for HaCaT keratinocytes; S. Ikawa (Tohoku University) for adenoviral vectors; and M. Sagai (Aomori University of Health and Welfare) for DEPs. Supported by the Japan Society for the Promotion of Science (KAKENHI 25840001 and 15K08257 to E.H.K.; 25461688 to E.O.; 22118002, 24249015 and 26111002 to M.Y.; and AMED-CREST (chronic inflammation) to M.Y.), the Mitsubishi Foundation (M.Y.) and the Takeda Science Foundation (M.Y.).

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T.H., E.H.K. and M.Y. designed the study; T.H. performed the experiments involving mice and cells, analyzed the data and wrote the paper; E.O. and R.O. performed ChIP sampling and experiments with human specimens; E.H.K. supervised the study, performed ChIP analyses, analyzed the data and wrote the paper; T.S., T.F. and S.A were involved in the study design; R.F. organized and K.N. supervised the deep sequencing; T.N. performed bioinformatics analyses; and M.Y. supervised the project and wrote the paper.

Corresponding authors

Correspondence to Eri H Kobayashi or Masayuki Yamamoto.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Allergic inflammation in AhR-CA mice.

(a) Gate strategy for assessing allergic inflammatory cells in the skin of AhR-CA mice. CD4+ T cells were gated on CD45+SSClowFSClowCD3+CD4+ cells. Mast cells were gated on CD45+CD3B220SSChiFSChiCD117+FcɛRIα+. ILC2s were gated on CD45+SSClowFSClowLin(CD3CD5B220CD11bGr-1NK1.1FcɛRIα) CD25+IL-33Rα+CD127+KLEG1+ cells. Eosinophils were gated on CD45+CD3B220SSChiFSClowCD11b+Siglec-F+ cells. Basophils were gated on CD45+CD3B220CD117CD49b+FcɛRIα+ cells. (b) Number of inflammatory cells detected in the skin of 5 AhR-CA mice and that of 5 WT littermates. Dots represent individual mice. (c) Relative expression of barrier-related genes in the epidermis of 5 AhR-CA mice and 5 WT littermates; box-and-whisker plot (line, median; box, 25th to 75th percentiles; bar, minimum to maximum). (d) Relative expression of Tslp, Il33 and Cyp1a1 in AhR-CA overexpressing keratinocytes; each dot represents an independent sampling, n=3. (e) AhR-CA ChIP-qPCR results from 3 independent samplings. (f, g) Immunostaining of the skin for TSLP (f) and IL-33 (g). Dotted line, the epidermis-dermis boundary; scale bar, 50 µm for f and 100 µm for g; representative images of 3 mice each. (h) Intracellular cytokine staining of CD4+ T cells isolated from regional lymph nodes of AhR-CA mice and WT littermates (5 mice each). (i) Dot-plot presentation of the intracellular cytokine staining observed in h. Dots represent individual mice. Data in b, d, and i; lines represent the mean; unpaired t-test; *p <0.05, **p < 0.01 and ***p<0.001.

Supplementary Figure 2 Influence of skin-barrier destruction and cytokine expression on AhR-CA mouse phenotypes.

(a) OVA uptake by MHC class II+ (MHCII+) antigen-presenting cells at the cortex of regional lymph nodes. Scale bar, 20 µm; 3 mice each. (b) Number of OVA+ and OVA+MHCII+ cells observed in a. (c-e) Relative mRNA expressions of Ephb2 (c), Artn (d), and St3gal3 (e). The expressions of Ephb2 and St3gal3 were evaluated in the RT-qPCR analysis of epidermal samples from neonatal AhR-CA mice compared with their expression in samples from wild-type littermates (5 mice each). Artn expression was examined in the skin from WT and AhR-CA mice with or without nail-clipping (6 mice each). (f) Relative expression of AD-related genes at the rostral back after Artemin-neutralization (4 mice each). (g-i) Appearance (g, Scale bar, 10 mm), number of scratching behaviors in 10 min (h) and alloknesis score (i, lines represent the median; Mann-Whitney U test) of 4 Tslp-KO, 5 AhR-CA, and 6 AhR-CATslp-KO compound mice. Data in b-f, and h, dots represent individual mice; lines represent the mean; unpaired t-test; *p < 0.05 and **p < 0.01.

Supplementary Figure 3 Exposure to air pollutants induces expression of Tslp and Il33 in keratinocytes.

(a) Knockout efficiency determined via PCR of the Ahr gene using isolated epidermal samples of Ahrfl/fl mice and Ahrfl/flKrt5-Cre mice (dots represent individual mice, 5 mice each). (b, c) Relative expressions of Tslp, Il33 and Cyp1a1 in mouse primary keratinocytes exposed to different concentrations of benzo[a]pyrene (B[a]P; 3 independent samplings; b) and in 1 µM B[a]P-exposed mouse primary keratinocytes with or without AhR knockdown (3 independent samplings, c). (d) Relative expression of CYP1A1 in HaCaT cells exposed to FICZ (5 independent samplings). (e) Relative expression of TSLP, IL33, FLG and CYP1A1 in differentiated or undifferentiated HEKns exposed to DMBA or FICZ (6 independent samplings). Data in a - d, coral lines represent the mean. Data in e, box-and-whisker plot (line, median; box, 25th to 75th percentiles; bar, minimum to maximum). Data in a-e, unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001.

Supplementary Figure 4 Evaluation of CYP1A1 expression and hyper-innervation in human skin.

(a) Representative immunostaining for CYP1A1 in the specimens classified as –, + and ++. Images from the same experiments as in Fig. 7g and Supplementary Table 1. –, negative or positive only in basal layer; +, positive in less than the half of the epidermis; ++, positive in more than the half of the epidermis. Immunostaining for TSLP in the same specimens are presented in the lower panels. Scale bars, 100 µm. (b) Immunostaining for neuronal marker PGP9.5 in skin samples of normal subjects, AD patients, and contact dermatitis patients. Dotted line, the epidermis-dermis boundary; scale bar, 20 µm; representative images of 3 individuals each.

Supplementary Figure 5 Epidermal activation of AhR by air pollutants causes AD-like phenotypes through artemin expression and hyper-innervation into the epidermis.

Schema of AhR-mediated development and the exacerbation of AD. Note that AhR is activated by air pollutants, such as traffic-derived particulate matter. Activated AhR induces the expression of TSLP, IL-33 and ARTEMIN in keratinocytes. ARTEMIN induces hyper-innervation of the epidermis by sensory nerves, resulting in alloknesis. Subsequent scratching behaviors lead to barrier damage and increased antigen penetration, resulting in enhanced sensitization that promotes a predisposition to other allergic diseases.

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Hidaka, T., Ogawa, E., Kobayashi, E. 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). https://doi.org/10.1038/ni.3614

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