146 Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis

Tsuji, Gaku; Hachiya, Akiko; Oda, Masanao; Takao, Masaki; Yan, Xianghong; Nakahara, Takeshi; Uchi, Hiroshi; Furue, Masutaka

doi:10.1016/j.jid.2017.07.456

Cited by 1 publication

(1 citation statement)

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“…For instance, Van den Bogaard et al used skin organoids derived from primary keratinocytes of patients with AD and showed that coal tar acted through AHR to restore FLG expression and other markers of keratinocyte differentiation (6). Furthermore, Tsuji et al showed that in primary human keratinocytes, AHR activation with FICZ and Glyteer (soybean tar) could induce the expression of the barrier gene FLG and that FICZ and Glyteer can restore the FLG expression that was reduced by IL-4 treatment, and that AHR activation mediated these effects via OVOL1 (7). Notably, filaggrin (FLG) is a key protein involved in the skin barrier, and mutations in FLG are associated with AD (61).…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis

Proper,

Dwyer,

Appiagyei

et al. 2024

Front. Allergy

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IntroductionAtopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD; however, the mechanism by which AHR partially ameliorates AD is not well known.MethodsGene expression data from human biopsies were analyzed, and compared to gene expression from RNA-sequencing in our in-vitro HaCaT cell model system. Western blot, ELISA qRT-PCR were used to further explore the relationship between AHR and IL-13 signaling in HaCaT cells.ResultsThe AHR target gene CYP1A1 was decreased in lesional skin compared with healthy control skin (p = 4.30 × 10−9). Single-cell RNA sequencing (scRNAseq) demonstrated increased AHR expression (p < 1.0 × 10−4) and decreased CYP1A1 expression in lesional AD keratinocytes compared with healthy control keratinocytes (p < 0.001). Activation of AHR by AHR agonists in HaCaT cells reversed IL-13-dependent gene expression of several key genes in AD pathogenesis, most notably the eosinophil chemoattractant CCL26 (eotaxin-3). Differentially expressed genes in keratinocytes of patients with AD substantially overlapped with genes regulated by AHR agonists from HaCaT cells by RNAseq, but in reverse direction. Mechanistically, there was evidence for direct transcriptional effects of AHR; AHR binding motifs were identified in the differentially expressed genes from lesional AD keratinocytes compared to control keratinocytes, and AHR activation did not modify IL-13-dependent signal transducer and activator of transcription 6 (STAT6) translocation to the nucleus.DiscussionTogether, these data suggest that the AHR pathway is dysregulated in AD and that AHR modulates IL-13 downstream signaling in keratinocytes through genome-wide, transcriptional regulatory effects.

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Section: Discussionmentioning

confidence: 99%