The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

Bogaard, Ellen H. van den; Esser, Charlotte; Perdew, Gary H.

doi:10.1111/exd.14409

Cited by 18 publications

(10 citation statements)

References 74 publications

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“…12 Interestingly, the skin microbiome produces tryptophane metabolites that can also activate AhR, and may contribute to homeostasis of normal skin. 13,14 Tapinarof can activate the nuclear factor erythroid 2-related factor antioxidant signalling pathway, and has anti-bacterial properties. 15,16 Notably, AhR modulation to treat skin diseases has been used for more than a century, as tar, previously a common treatment for psoriasis, has been shown to be an AhR agonist.…”

Section: Ech a N Ism Of Ac Tionmentioning

confidence: 99%

“…The mechanism of AhR‐mediated cellular regulation is complex and still being elucidated; AhR effect on gene expression depends on the ligand to which it binds 12 . Interestingly, the skin microbiome produces tryptophane metabolites that can also activate AhR, and may contribute to homeostasis of normal skin 13,14 . Tapinarof can activate the nuclear factor erythroid 2‐related factor antioxidant signalling pathway, and has anti‐bacterial properties 15,16 .…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research

Bissonnette

Proulx

Jack

et al. 2023

Acad Dermatol Venereol

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Tapinarof is a topical, aryl‐hydrocarbon receptor agonist that has recently received FDA‐approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.

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Section: Ech a N Ism Of Ac Tionmentioning

confidence: 99%

Section: Mechanism Of Actionmentioning

confidence: 99%

Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research

Bissonnette

Proulx

Jack

et al. 2023

Acad Dermatol Venereol

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“…The AhR can be activated by metabolites of bacteria such as Pseudomonas aeruginosa [10] or members of the skin microbiota, such as Malassezia yeasts [16]. Although the role of the AhR in cutaneous defense is still emerging there is growing evidence that it plays an important role in skin-microbe interaction [14]. Several reports have shown that the AhR is crucial for the maintenance of skin barrier function [17, 18].…”

Section: Introductionmentioning

confidence: 99%

“…The AhR is a ligand-activated transcription factor involved in xenobiotic metabolism, epidermal barrier formation, immune signaling, and immune cell differentiation [10][11][12]. AhR is activated upon binding of various low-molecularweight ligands; the receptor is expressed in various tissues, particularly high expression is found in the liver and in barrier organs such as gut and skin [13,14]. There is increasing evidence that the AhR plays a major role in host defense [11,13,15].…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus Activates the Aryl Hydrocarbon Receptor in Human Keratinocytes

Stange¹,

Rademacher²,

Drerup³

et al. 2022

J Innate Immun

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Staphylococcus aureus is an important pathogen causing various infections, including – as most frequently isolated bacterium – cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to S. aureus by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of S. aureus, the mechanisms underlying the interplay between S. aureus and keratinocytes are still emerging. Here, we report that S. aureus induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by S. aureus was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) <2 kDa secreted by S. aureus. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6, and IL-1beta as cytokines induced in an AhR-dependent manner in S. aureus-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6, and IL-1beta upon stimulation with living S. aureus. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen S. aureus in keratinocytes.

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“…Short-lived AHR ligands include UV-induced endogenous tryptophan metabolites [11] (hence the postulated role for AHR-mediated therapeutic effects of UV therapy in PSo). Other metabolites can be formed by members of the skin's microbiome, and dietary plant constituents, as well as several pharmaceutics [12][13][14][15]. Upon activation, AHR signaling is known to regulate a plethora of cellular processes, e.g., embryonic development [16], keratinocyte proliferation and differentiation [17], epidermal barrier formation [14,18], immune cell development [19], angiogenesis [20], and many more [16,18,19,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Carboxamide Derivatives Are Potential Therapeutic AHR Ligands for Restoring IL-4 Mediated Repression of Epidermal Differentiation Proteins

Rikken

Brink

Vlijmen-Willems

et al. 2022

IJMS

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Atopic dermatitis (AD) is a common T-helper 2 (Th2) lymphocyte-mediated chronic inflammatory skin disease characterized by disturbed epidermal differentiation (e.g., filaggrin (FLG) expression) and diminished skin barrier function. Therapeutics targeting the aryl hydrocarbon receptor (AHR), such as coal tar and tapinarof, are effective in AD, yet new receptor ligands with improved potency or bioavailability are in demand to expand the AHR-targeting therapeutic arsenal. We found that carboxamide derivatives from laquinimod, tasquinimod, and roquinimex can activate AHR signaling at low nanomolar concentrations. Tasquinimod derivative (IMA-06504) and its prodrug (IMA-07101) provided full agonist activity and were most effective to induce FLG and other epidermal differentiation proteins, and counteracted IL-4 mediated repression of terminal differentiation. Partial agonist activity by other derivatives was less efficacious. The previously reported beneficial safety profile of these novel small molecules, and the herein reported therapeutic potential of specific carboxamide derivatives, provides a solid rationale for further preclinical assertation.

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The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 18 publications

References 74 publications

Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research

Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research

<b><i>Staphylococcus aureus</i></b> Activates the Aryl Hydrocarbon Receptor in Human Keratinocytes

Carboxamide Derivatives Are Potential Therapeutic AHR Ligands for Restoring IL-4 Mediated Repression of Epidermal Differentiation Proteins

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