Aryl hydrocarbon receptor/nuclear factor E2‐related factor 2 (AHR/NRF2) signalling: A novel therapeutic target for atopic dermatitis

Hwang, Jonwei; Newton, Edita M; Hsiao, Jennifer L.; Shi, Vivian Y.

doi:10.1111/exd.14541

Cited by 19 publications

(17 citation statements)

References 126 publications

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“…Tanaka et al reported that Th2 cytokines such as IL-4 and IL-13 can increase the mRNA and protein expression of AhR in B cells and keratinocytes 24 . This suggests a mutually compensatory regulation between Th2 cells, B cells and AhR signaling 9 . In this study, we found that AhR + CD19 + B cells were increased in PBMCs but not signi cantly increased in skin lesions of AD, suggesting that AhR may be involved in biological functions of B cells in AD.…”

Section: Discussionmentioning

confidence: 95%

“…Atopic dermatitis is an eczematous skin disorder characterized by Th2-deviated skin in ammation, barrier disruption and chronic pruritus 14 . Increased Th2 cytokines such as IL-4, IL-5, IL-13 and IL-33 were found in AD and the Th17/Th22 axis have also been implicated 9 . In this study, we found that AhR, IL-22 and IL-17 mRNA were increased in PBMCs of AD.…”

Section: Discussionmentioning

confidence: 99%

“…The AhR expression is found to be signi cantly increased in PBMCs and lesional skin of patients with AD 8 . AhR modulation can lead to potential therapeutic effects 9 .…”

Section: Introductionmentioning

confidence: 99%

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Unbalanced aryl hydrocarbon receptor expression in peripheral and lesional T cell subsets of atopic dermatitis

Yong-fang

Zhao

Zhang

2022

Preprint

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Conclusion AhR was highly expressed in subpopulations of T cells in peripheral blood and skin lesions of AD, suggesting that AhR might contribute to the pathogenesis of AD. Background and Objective The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which is involved in the pathogenesis of a variety of skin diseases such as atopic dermatitis (AD). In this study, we aimed to study the AhR-expressing cells in T helper 17 (Th17), T helper 22 (Th22), regulatory T cells (Treg) and B cells in peripheral blood and in AD skin lesions. Methods Twenty AD patients defined according to the Chinese criteria of atopic dermatitis and eighteen healthy subjects were included in our study. The AhR-expressing Th17, Th22, Treg and total B cells in peripheral blood was measured by flow cytometry. The AhR+ Th17 cells and AhR+ Th22 cells in AD skin lesions was measured by immunofluorescence. The mRNA of AhR, interleukin (IL)-22, IL-17A, IL-10, Foxp3, RORγT and TGF-β in peripheral blood mononuclear cells (PBMCs) was measured by real-time quantitative polymerase chain reaction. Results The expression of AhR in peripheral CD4+ T cells, Th22 cells, Treg cells and total B cells was significantly increased in AD. AhR+IL-17A+ and AhR+IL-22+ lymphocytes were also increased in AD skin lesions. The mRNA levels of AhR, IL-22 and IL-17A in PBMCs in AD patients were significantly higher. AhR mRNA levels in PBMCs positively correlated with peripheral basophil count, peripheral eosinophils count and mRNA levels of IL-22.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Unbalanced aryl hydrocarbon receptor expression in peripheral and lesional T cell subsets of atopic dermatitis

Yong-fang

Zhao

Zhang

2022

Preprint

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“…Since the dysfunction of NRF2 has been reported to potentiate skin inflammation ( 28 ), activators of the AHR-NRF2 axis should be candidate therapeutic agents for inflammatory skin diseases such as AD and psoriasis ( 14 ). Specifically, tapinarof is a potential new topical treatment for AD and psoriasis as a therapeutic AHR-modulating agent ( 29 ). It has been reported that tapinarof exerts anti-inflammatory effects by activating NRF2 via AHR in NHEKs ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

et al. 2022

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Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

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“…A common error by many authors is that benvitimod is considered the same as tapinarof. Indeed, the active ingredient is the same (3,5-dihydroxy-4- isopropyl-trans-stilbene) and is isolated from the bacterium Photorhabdus luminescens [ 52 ]. However, tapinarof cream 1% comprises a novel vehicle with specific excipients to enhance efficacy, drug delivery and patient acceptability.…”

Section: Aryl Hydrocarbon Receptor Agonistsmentioning

confidence: 99%

New and Upcoming Topical Treatments for Atopic Dermatitis: A Review of the Literature

Sideris

Paschou

Bakirtzi

et al. 2022

JCM

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Atopic dermatitis (AD) is a chronic inflammatory dermatosis with periods of exacerbation and remissions. AD is characterized by intense, persistent pruritus and heterogeneity in clinical symptomatology and severity. Therapeutic goals include the amelioration of cutaneous eruptions, diminishing relapses and eventually the disease burden. To date, topical corticosteroids (TCS) and calcineurin inhibitors (TCI) have yet been deemed the mainstay of topical treatments in AD management. Nevertheless, despite their indisputable efficiency, TCS and TCI are not indicated for continuous long-term use given their safety profile. While research in AD has concentrated predominantly on systemic therapies, more than 30 novel topical compounds are under development. The existing data appear encouraging, with some regimens that are already FDA-approved (ruxolitinib was the most recent in September 2021) and several pharmaceutical pipeline products for mild-to-moderate AD that are in an advanced stage of development, such as tapinarof, difamilast and roflumilast. Larger, long-term studies are still required to evaluate the efficacy and safety of these novel compounds in the long run and weigh their advantages over present treatments. In this review, we aim to provide an overview of the latest knowledge about AD topical treatments, echoing upcoming research trends.

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Aryl hydrocarbon receptor/nuclear factor E2‐related factor 2 (AHR/NRF2) signalling: A novel therapeutic target for atopic dermatitis

Cited by 19 publications

References 126 publications

Unbalanced aryl hydrocarbon receptor expression in peripheral and lesional T cell subsets of atopic dermatitis

Unbalanced aryl hydrocarbon receptor expression in peripheral and lesional T cell subsets of atopic dermatitis

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

New and Upcoming Topical Treatments for Atopic Dermatitis: A Review of the Literature

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