Regulation of Retinoid-Mediated Signaling Involved in Skin Homeostasis by RAR and RXR Agonists/Antagonists in Mouse Skin

Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Álvarez, Susana; Álvarez, Rosana; Törőcsik, Dániel; Lera, Ángel R. de; Rühl, Ralph

doi:10.1371/journal.pone.0062643

Cited by 47 publications

(57 citation statements)

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“…Increased RARγ-RXR mediated signaling may be initiated in the skin via internal or external triggers (33,37). We confirm by this that retinoids / vitamin A are important triggers for atopic sensitization (38)(39)(40).…”

Section: Discussionsupporting

confidence: 73%

“…Especially the retinoid receptors (RAR) RARα and RARγ are crucial for skin homeostasis and skin inflammation (16) and application of selective synthetic RARγ ligands induced epidermal hyperproliferation (33). In addition, ablated RXRαβ (ep-/-) keratinocytes in mice generate a chronic dermatitis which displays high similarity to human AD (34).…”

Section: Discussionmentioning

confidence: 99%

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TSLP expression in the skin is mediated via RARγ-RXR pathways

et al. 2016

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TSLP is an important trigger and initiator for various atopic diseases mainly atopic dermatitis (AD). Activators of nuclear hormone receptors like bioactive vitamin A and D derivatives are known to induce TSLP up-regulation in the skin. In this study, various combinations of synthetic specific agonists and antagonists of the retinoic acid receptors (RARs), retinoid X receptors (RXRs) and vitamin D receptor (VDR) were topically administered to mice. The aim of the study was to elucidate via which nuclear hormone receptor pathways TSLP is regulated and how this regulation is connected to the development and phenotype of atopic dermatitis. TSLP expression was monitored using QRT-PCR and serum TSLP levels using ELISA. Synthetic agonists of the VDR and RARγ as well as the natural agonist all-trans retinoic acid (ATRA) increased TSLP expression in the skin, while an RXR agonist was not active. Treatments with antagonists of RXRs and RARs in addition to RARα-agonists reduced skin TSLP expression. Strong activation was found after a combination of a VDR and an RXR agonist (ca. 5 times induction) and even stronger by an RARγ and an RXR agonist treatment (ca. 48 times induction). We conclude that besides VDR-mediated signaling mainly RARγ-RXR mediated pathways in the skin are important patho-physiological triggers for increased skin TSLP expression. We conclude that topical synthesized retinoids stimulated by internal or external triggers or topically applied induce TSLP production and are thereby important triggers for atopic dermatitis prevalence.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

TSLP expression in the skin is mediated via RARγ-RXR pathways

et al. 2016

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“…In fact, KRT4, HBEGF and CYP26A1/B1 are considered to be retinoid target genes 65 (Gericke et al ., 2013) where KRT 4 is a marker for keratinocyte differentiation 66 (Wanner et al . 1996), CYP26 for retinoid metabolism and HBEGF for increased keratinocyte proliferation and epidermal thickness 8.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional changes in organoculture of full‐thickness human skin following topical application of all‐trans retinoic acid

Gillbro

Al-Bader

Westman

et al. 2014

Intern J of Cosmetic Sci

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SynopsisObjectiveRetinoids are used as therapeutic agents for numerous skin diseases, for example, psoriasis, acne and keratinization disorders. The same substances have also been recognized in the treatment for hyperpigmentation disorders such as melasma.Other studies on photo-damaged skin have shown that retinoids reduce wrinkles, surface roughness, mottled pigmentation, and visual skin appearance as a whole. We tested the hypothesis that an organoculture of full-thickness human skin could be used as a preclinical model to investigate the retinoid transcriptional profile in human skin in vitro.MethodsFull-thickness skin explants were exposed to topically applied all-trans retinoic acid (RA) for 24 h. The gene expression profile was analysed using oligonucleotide microarrays, and data were validated with real-time (RT) PCR.ResultsWe showed that the expression of 93 genes was significantly altered more than twofold. Several of the altered genes, for example, KRT4, CYP26 and LCN2, have previously been shown to be affected by RA in keratinocyte monocultures, reconstructed epidermis and skin biopsies from patients treated topically or orally with RA. In addition, genes, such as SCEL, NRIP1, DGAT2, RDH12 EfnB2, MAPK14, SAMD9 and CEACAM6 not previously reported to be affected by RA in human skin, were identified for the first time in this study.ConclusionThe results in the present study show that full-thickness human explants represent a valuable pre-clinical model for studying the effects of retinoids in skin.RésuméObjectifLes rétinoïdes sont utilisés comme agents thérapeutiques pour de nombreuses maladies de la peau, p.ex. le psoriasis, l'acné et les troubles de la kératinisation. Les mêmes substances ont également été reconnues dans le traitement des troubles de l' hyperpigmentation tels que le melasma.D'autres études sur la peau photo-endommagée ont montré que les rétinoïdes réduisent les rides, la rugosité de la surface, la pigmentation tachetée, et l'aspect visuel de la peau dans son ensemble. Nous avons testé l'hypothèse selon laquelle une organoculture de épaisseur intégrale de la peau humaine pourrait être utilisée comme modèle préclinique pour étudier le profil transcriptionnel des rétinoïdes dans la peau humaine in vitro.MéthodesDes explants de peau intégrale ont été exposés à l'application topique de all-trans acide rétinoïque (RA) pendant 24 heures. Le profil d' expression des gènes a été analysé en utilisant des puces DNA array et les données ont été validées par (RT) -PCR.ResultatsNous avons montré que l'expression de 93 gènes a été modifiée de façon significative par plus d'un facteur 2. Plusieurs des gènes modifiés par exemple KRT4, CYP26 et LCN2 ont été montrés précédemment d'être affectés par RA dans les monocultures de kératinocytes, dans l'épiderme reconstruit et dans des biopsies cutanées de patients traités par voie topique ou par voie orale avec RA. En outre, des gènes tels que SCEL, NRIP1, DGAT2, RDH12 EfnB2, MAPK14, SAMD9 et CEACAM6 non signalés précédemment, sont touchés par RA dans la peau ...

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“…PMA is regarded as a potent tumor promoter and it is often used to activate the protein kinase C (PKC) pathway, which is involved in keratinocyte proliferation and differentiation [60,61]. RA signaling via retinoic acid receptor, has been shown to play a role in skin cell proliferation, differentiation, apoptosis, and epidermal barrier function and it is often used for treatment of skin aging [62][63][64][65]. Calcium has been shown to up-regulate differentiationand ribosome protein-related genes and down-regulate genes involved in metabolism, DNA repair, transcription, and translation in primary human keratinocytes [66].…”

Section: Discussionmentioning

confidence: 99%