Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation

Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.

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676 Minimum role of filaggrin-gene mutations in the skin barrier function of atopic dermatitis

Journal of Investigative Dermatology ◽

10.1016/j.jid.2018.03.685 ◽

2018 ◽

Vol 138 (5) ◽

pp. S115

Author(s):

M. Ota ◽

T. Sasaki ◽

T. Ebihara ◽

S. Murata ◽

S. Kaneko ◽

...

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Gene Mutations ◽

Skin Barrier ◽

Skin Barrier Function

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Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis

Journal of Clinical Medicine ◽

10.3390/jcm9113741 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3741

Author(s):

Masutaka Furue

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Coal Tar ◽

Calcineurin Inhibitors ◽

Skin Barrier ◽

Skin Inflammation ◽

Interleukin 4 ◽

Skin Barrier Function ◽

Barrier Dysfunction ◽

Therapeutic Implications

Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction, and chronic pruritus. As the anti-interleukin-4 (IL-4) receptor α antibody dupilumab improves all three cardinal features of AD, the type 2 cytokines IL-4 and especially IL-13 have been indicated to have pathogenic significance in AD. Accumulating evidence has shown that the skin barrier function is regulated via competition between the aryl hydrocarbon receptor (AHR) axis (up-regulation of barrier) and the IL-13/IL-4‒JAK‒STAT6/STAT3 axis (down-regulation of barrier). This latter axis also induces oxidative stress, which exacerbates inflammation. Conventional and recently developed agents for treating AD such as steroid, calcineurin inhibitors, cyclosporine, dupilumab, and JAK inhibitors inhibit the IL-13/IL-4‒JAK‒STAT6/STAT3 axis, while older remedies such as coal tar and glyteer are antioxidative AHR agonists. In this article, I summarize the pathogenic and therapeutic implications of the IL-13/IL-4‒JAK‒STAT6/STAT3 axis and the AHR axis in AD.

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The role of skin barrier function in atopic dermatitis: an update

Expert Review of Dermatology ◽

10.1586/edm.12.17 ◽

2012 ◽

Vol 7 (3) ◽

pp. 247-257 ◽

Cited By ~ 6

Author(s):

Regina Fölster-Holst ◽

Stephan Dähnhardt-Pfeiffer ◽

Dorothee Dähnhardt ◽

Ehrhardt Proksch

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Skin Barrier ◽

Skin Barrier Function

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Hypo-osmotic Shock-Induced Subclinical Inflammation of Skin in a Rat Model of Disrupted Skin Barrier Function

Biological Research For Nursing ◽

10.1177/1099800414532827 ◽

2014 ◽

Vol 17 (2) ◽

pp. 135-141 ◽

Cited By ~ 5

Author(s):

Chihiro Kishi ◽

Takeo Minematsu ◽

Lijuan Huang ◽

Yuko Mugita ◽

Aya Kitamura ◽

...

Keyword(s):

Barrier Function ◽

Inflammatory Responses ◽

Osmotic Shock ◽

Skin Barrier ◽

Skin Inflammation ◽

The Elderly ◽

Basic Mechanism ◽

Skin Barrier Function ◽

Inflammatory Reactions ◽

C Fibers

Aging disrupts skin barrier function and induces xerosis accompanied by pruritus. In many cases, elderly patients complain of pruritus during skin hygiene care, a condition called aquagenic pruritus of the elderly (APE). To date, the pathophysiology and mechanism of action of APE have not been elucidated. We conducted the present study to test the hypothesis that hypo-osmotic shock of epidermal cells induces skin inflammation and elongation of C-fibers by nerve growth factor β (NGFβ) as a basic mechanism of APE. The dorsal skin of HWY rats, which are a model for disrupted skin barrier function, was treated with distilled water (hypotonic treatment [Hypo] group) or normal saline (isotonic treatment [Iso] group) by applying soaked gauze for 7 days. Untreated rats were used as a control (no-treatment [NT] group). Histochemical and immunohistochemical analyses revealed inflammatory responses in the epidermis and the dermal papillary layer in the Hypo group, while no alterations were observed in the Iso or NT groups. Induction of expression and secretion of NGFβ and elongation of C-fibers into the epidermis were found in the Hypo group. In contrast, secretion of NGFβ was significantly lower and elongation of C-fibers was not observed in the Iso group. These results suggest that hypo-osmotic shock–induced inflammatory reactions promote hypersensitivity to pruritus in skin with disrupted barrier function.

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A Novel Multi-Action Emollient Plus Cream Improves Skin Barrier Function in Patients with Atopic Dermatitis: In vitro and Clinical Evidence

Skin Pharmacology and Physiology ◽

10.1159/000513055 ◽

2021 ◽

Vol 34 (1) ◽

pp. 8-18

Author(s):

Marika Quadri ◽

Roberta Lotti ◽

Laura Bonzano ◽

Silvana Ciardo ◽

Mario Bruno Guanti ◽

...

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Randomized Study ◽

Skin Barrier ◽

Lower Limbs ◽

Skin Barrier Function ◽

Tape Stripping ◽

Epidermal Thickness ◽

Epidermal Homeostasis

Background: Emollients capable of restoring the skin barrier function would extend their role beyond basic maintenance therapy in atopic dermatitis (AD). Objectives: Investigate the effect of a novel emollient plus cream (EC; Dermoflan®) on the skin barrier in vitro and in patients with mild-to-moderate AD. Methods: The effect of EC on the skin barrier recovery was evaluated using a tape-stripping (TS) model. After TS, organ cultures were treated with EC (undiluted or diluted 1:1 with water) and analyzed at 18–120 h using hematoxylin and eosin, Oil Red O, immunohistochemical, and immunofluorescent techniques. In a double-blind, randomized study, EC or placebo was applied once daily for 2 months to antecubital folds of the upper and lower limbs of patients with mild-to-moderate AD in clinical remission. Epidermal thickness, vascularization, and epidermal hydration were assessed by optical coherence tomography and corneometry, respectively, at baseline, and 1 and 2 months following treatment initiation. Results: Following TS, EC treatment significantly increased epidermal thickness and lipid content versus diluent in the skin organ culture, as well as claudin-1, involucrin, and caspase-14 expression, suggesting skin barrier repair. EC treatment also decreased keratin-16 expression and increased levels of Toll-like receptors 1 and 2 versus diluent, suggesting involvement in regulating the epidermal immune response. In 20 patients randomized 1:1 to EC or placebo, EC treatment at the elbow fold/popliteal fossa significantly decreased epidermal thickness after 2 months, and the number of blood vessels at the elbow fold after 1 and 2 months, versus placebo. EC significantly improved the skin hydration after 2 months versus baseline. Conclusions: This novel multi-action EC may help to restore epidermal homeostasis and improve the skin of patients with AD. Results indicate that this novel multi-action EC could be a valid adjuvant therapy in patients with AD. Key Message: Novel multi-action emollient cream helps to restore epidermal homeostasis and improves the skin affected by AD.

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Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study

International Journal of Molecular Sciences ◽

10.3390/ijms221910189 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10189

Author(s):

Young In Lee ◽

Sang Gyu Lee ◽

Jemin Kim ◽

Sooyeon Choi ◽

Inhee Jung ◽

...

Keyword(s):

Atopic Dermatitis ◽

Hyaluronic Acid ◽

Barrier Function ◽

Ex Vivo ◽

Therapeutic Option ◽

Skin Barrier ◽

Transepidermal Water Loss ◽

Skin Barrier Function ◽

Hydrolyzed Collagen

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECMTM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin’s barrier function. The study revealed the clinical and laboratory efficacy of H.ECMTM liposome in reducing itching and improving the skin’s barrier integrity. Thus, the use of H.ECMTM liposome can be considered a therapeutic option for dry and eczema-prone skin.

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Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS

The Journal of Lipid Research ◽

10.1194/jlr.ra120000671 ◽

2020 ◽

Vol 61 (6) ◽

pp. 884-895 ◽

Cited By ~ 2

Author(s):

Momoko Kawana ◽

Masatoshi Miyamoto ◽

Yusuke Ohno ◽

Akio Kihara

Keyword(s):

Stratum Corneum ◽

Barrier Function ◽

Normal Skin ◽

Skin Barrier ◽

Hydroxyl Group ◽

Skin Barrier Function ◽

Elongation Cycle ◽

Barrier Formation ◽

Ceramide Synthesis

Ceramides are the predominant lipids in the stratum corneum (SC) and are crucial components for normal skin barrier function. Although the composition of various ceramide classes in the human SC has been reported, that in mice is still unknown, despite mice being widely used as animal models of skin barrier function. Here, we performed LC/MS/MS analyses using recently available ceramide class standards to measure 25 classes of free ceramides and 5 classes of protein-bound ceramides from human and mouse SC. Phytosphingosine- and 6-hydroxy sphingosine-type ceramides, which both contain an additional hydroxyl group, were abundant in the human SC (35% and 45% of total ceramides, respectively). In contrast, in mice, phytosphingosine- and 6-hydroxy sphingosine-type ceramides were present at ∼1% and undetectable levels, respectively, and sphingosine-type ceramides accounted for ∼90%. In humans, ceramides containing α-hydroxy FA were abundant, whereas ceramides containing β-hydroxy or ω-hydroxy FA were abundant in mice. The hydroxylated β-carbon in β-hydroxy ceramides was in the (R) configuration. Genetic knockout of β-hydroxy acyl-CoA dehydratases in HAP1 cells increased β-hydroxy ceramide levels, suggesting that β-hydroxy acyl-CoA, an FA-elongation cycle intermediate in the ER, is a substrate for β-hydroxy ceramide synthesis. We anticipate that our methods and findings will help to elucidate the role of each ceramide class in skin barrier formation and in the pathogenesis of skin disorders.

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