Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis

Atopic Dermatitis is a chronic inflammatory skin disease that affects a large number of children and adults. The disease results from an interaction between genetic predisposition, host environment, skin barrier defects, and immunological factors. A major aggravating factor associated with Atopic Dermatitis is the presence of microorganisms on the patient's skin surface. Staphylococcus aureus and Streptococcus pyogenes, for instance, can exacerbate chronic skin inflammation. As a result, antimicrobials have often been prescribed to control the acute phase of the disease. However, increased bacterial resistance to antimicrobial agents has made it difficult for dermatologists to prescribe appropriate medication. In the presence of disseminated dermatitis with secondary infection, systemic antibiotics need to be prescribed; however, treatment should be individualized, in an attempt to find the most effective antibiotic with fewer side effects. Also, the medication should be used for as short as possible in order to minimize bacterial resistance.

Download Full-text

Ex-Vivo Skin Explant Culture Is a Model for TSLP-Mediated Skin Barrier Immunity

Life ◽

10.3390/life11111237 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1237

Author(s):

Thomas Bauer ◽

Daniela Gubi ◽

Jörg Klufa ◽

Philipp Novoszel ◽

Martin Holcmann ◽

...

Keyword(s):

Atopic Dermatitis ◽

Ex Vivo ◽

Skin Barrier ◽

Skin Inflammation ◽

The Body ◽

Suitable Model ◽

Ex Vivo Model ◽

Egfr Inhibition ◽

Explant Cultures ◽

Barrier Immunity

The skin is the outermost barrier protecting the body from pathogenic invasion and environmental insults. Its breakdown initiates the start of skin inflammation. The epidermal growth factor (EGFR) on keratinocytes protects this barrier, and its dysfunction leads to atopic dermatitis-like skin disease. One of the initial cytokines expressed upon skin barrier breach and during atopic dermatitis is TSLP. Here, we describe the expression and secretion of TSLP during EGFR inhibition and present an ex-vivo model, which mimics the early events after barrier insult. Skin explants floated on culture medium at 32 °C released TSLP in parallel to the activation of the resident Langerhans cell network. We could further show the up-regulation and activation of the AP-1 family of transcription factors during atopic-like skin inflammation and its involvement in TSLP production from the skin explant cultures. Inhibition of the c-Jun N-terminal kinase pathway led to a dose-dependent blunting of TSLP release. These data indicate the involvement of AP-1 during the early stages of atopic-like skin inflammation and highlight a novel therapeutic approach by targeting it. Therefore, skin explant cultures mimic the early events during skin barrier immunity and provide a suitable model to test therapeutic intervention.

Download Full-text

Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome

Journal of Experimental Medicine ◽

10.1084/jem.20082242 ◽

2009 ◽

Vol 206 (5) ◽

pp. 1135-1147 ◽

Cited By ~ 322

Author(s):

Anaïs Briot ◽

Céline Deraison ◽

Matthieu Lacroix ◽

Chrystelle Bonnart ◽

Aurélie Robin ◽

...

Keyword(s):

Atopic Dermatitis ◽

Protease Inhibitor ◽

Adaptive Immune System ◽

Skin Barrier ◽

Skin Inflammation ◽

Nuclear Factor Κb ◽

Thymic Stromal Lymphopoietin ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Netherton Syndrome

Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type–related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor κB–mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor α, and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5−/− embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)–like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.

Download Full-text

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.

Download Full-text

Food allergy and atopic dermatitis

Journal of Food Allergy ◽

10.2500/jfa.2020.2.200018 ◽

2020 ◽

Vol 2 (1) ◽

pp. 35-38

Author(s):

Tina Banzon ◽

Donald Y.M. Leung ◽

Lynda C. Schneider

Keyword(s):

Atopic Dermatitis ◽

Food Allergy ◽

Immunoglobulin E ◽

Growth Failure ◽

Skin Barrier ◽

Clinical History ◽

Skin Inflammation ◽

Specific Ige ◽

Nutritional Deficiencies ◽

Detailed Clinical History

Atopic dermatitis (AD), characterized by intense pruritus, eczematous lesions, and a relapsing disease course, is a chronic inflammatory skin disease that affects both children and adults. AD often begins in infancy and is associated with atopic diseases in the personal or family history.1 Environmental factors may trigger AD by affecting the skin barrier and by triggering inflammation. The elicitation of T-helper type 2 cytokines further impairs the epidermal barrier and leads to the penetration of irritants and allergens into the epidermis and thereby perpetuating inflammation. The presence of AD and its severity has been shown to positively correlate with risk of developing food allergy (FA). Children with AD are estimated to be six times more likely to develop FA compared with their healthy peers. It has been reported that nearly 40% of children with moderate-to-severe AD have immunoglobulin E (IgE) mediated FA compared with only 6% in the general population. Although analysis of experimental data has linked skin inflammation in AD to FA, with food challenges reproducing symptoms and avoidance diets improving AD, elimination diets are not known to cure AD and may have unfavorable consequences, such as loss of tolerance, which leads to immediate-type allergy, including anaphylaxis, nutritional deficiencies, growth failure, and reduction of quality of life for the patient and family. Exacerbation of AD can be inaccurately attributed to foods. Individuals with AD are often sensitized to foods with positive testing results, however, able to tolerate the food. In light of widespread ordering and commercial availability of serum specific IgE for FA, testing for FA is recommended only if, from a detailed clinical history, immediate-type allergic symptoms occur with ingestion of food, or in infants with AD who do not improve with optimal skin care.

Download Full-text

Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section IV: Treatment Options for the Management of Atopic Dermatitis

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475418805721 ◽

2018 ◽

Vol 22 (1_suppl) ◽

pp. 21S-29S ◽

Cited By ~ 2

Author(s):

Gurbir Dhadwal ◽

Lorne Albrecht ◽

Robert Gniadecki ◽

Yves Poulin ◽

Jensen Yeung ◽

...

Keyword(s):

Atopic Dermatitis ◽

Topical Therapy ◽

Treatment Options ◽

Skin Barrier ◽

Skin Inflammation ◽

Skin Barrier Function ◽

Improve Quality ◽

Consensus Document ◽

Basic Care

The objectives of therapy for atopic dermatitis (AD) are to reduce skin inflammation and pruritus, restore skin barrier function, and improve quality of life (QoL). Treatments can be classified as moisturizing and basic care, topical therapy, phototherapy, and systemic therapy. In this review, we summarize the treatments for AD and recommendations for their use.

Download Full-text

Atopic dermatitis: experimentalmodels for study of pathogenesis and development of new methods of treatment

Rossiiskii Allergologicheskii ZHurnal ◽

10.36691/rja767 ◽

2011 ◽

Vol 8 (6) ◽

pp. 3-11

Author(s):

N N Shershakova ◽

A A Babakhin ◽

O G Elisyutina ◽

M R Khaitov ◽

N N Shershakova ◽

...

Keyword(s):

Atopic Dermatitis ◽

Skin Barrier ◽

Skin Inflammation ◽

Barrier Dysfunction ◽

Skin Injury ◽

Allergic Skin ◽

Promising Area ◽

Functional Peptides ◽

Methods Of Treatment

Atopic dermatitis (AD) is characterized by allergic skin inflammation. A hallmark of AD is dry itchy skin due, at least in part, to defects in skin genes that are important for maintaining barrier function. The pathogenesis of AD remains incompletely understood. A number of mouse models of AD have been developed. This review discusses these models and emphasizes the role of mechanical skin injury and skin barrier dysfunction in eliciting allergic skin inflammation. Also, we describe various approaches to the treatment of atopic dermatitis, the latest of which is the introduction of siRN A. Development of drugs based on siRN A using functional peptides is a promising area of research in allergology.

Download Full-text

Atopic Dermatitis: Preventing and Managing the Itch That Rashes, and a Case for the Multi-Theory Model (MTM) for Health Behavior Change for Educational Interventions

SKIN The Journal of Cutaneous Medicine ◽

10.25251/skin.5.5.3 ◽

2021 ◽

Vol 5 (5) ◽

pp. 462-473

Author(s):

Kayla Penny ◽

Manoj Sharma ◽

Amy E. Flischel ◽

Robert T. Brodell ◽

Vinayak K. Nahar

Keyword(s):

Atopic Dermatitis ◽

Health Behavior ◽

Management Strategies ◽

Skin Barrier ◽

Skin Inflammation ◽

Health Behavior Change ◽

Educational Interventions ◽

Theory Model ◽

Educational Strategies ◽

Use Behavior

Atopic dermatitis (AD) is a multifactorial disease affected by a host of genetic, environmental, socioeconomic and demographic influences, that induce the atopic immune response in predisposed individuals. Despite treatment with topical corticosteroids to reduce skin inflammation, emollients to improve the skin barrier, and avoidance of inflammatory triggers, many patients report progressive symptoms. Management strategies are developed as modifiable environmental influences are identified. Managing atopic dermatitis requires adaptive changes in health behavior involving the patient and often the caregiver. Multi-theory models (MTM) have not yet been used in AD interventions but may prove beneficial as they use behavior concepts to predict both initiation and sustenance in education health interventions. A comprehensive approach fosters such changes by using psychological and educational strategies as adjuncts to conventional therapy. This article reviews the challenges in managing AD and the potential impact of behavioral theories. This is designed to strengthen the argument for using an MTM model in future studies of AD.

Download Full-text

Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation

Cells ◽

10.3390/cells10113176 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3176

Author(s):

Nieves Fernández-Gallego ◽

Francisco Sánchez-Madrid ◽

Danay Cibrian

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Inflammatory Responses ◽

Normal Skin ◽

Skin Barrier ◽

Skin Inflammation ◽

In Vitro Assays ◽

Skin Barrier Function

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.

Download Full-text

Topical Administration of Melatonin-Loaded Extracellular Vesicle-Mimetic Nanovesicles Improves 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis

Biomolecules ◽

10.3390/biom11101450 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1450

Author(s):

Yoon Seon Kim ◽

Gyeongyun Go ◽

Chul-Won Yun ◽

Ji-Hye Yea ◽

Sungtae Yoon ◽

...

Keyword(s):

Atopic Dermatitis ◽

Transdermal Delivery ◽

Cell Activation ◽

Immune Cell ◽

Therapeutic Potential ◽

Skin Barrier ◽

Skin Inflammation ◽

Topical Administration ◽

Extracellular Vesicle ◽

Optimal Size

Atopic dermatitis (AD) is caused by multiple factors that trigger chronic skin inflammation, including a defective skin barrier, immune cell activation, and microbial exposure. Although melatonin has an excellent biosafety profile and a potential to treat AD, there is limited clinical evidence from controlled trials that support the use of melatonin as an AD treatment. The delivery of melatonin via the transdermal delivery system is also a challenge in designing melatonin-based AD treatments. In this study, we generated melatonin-loaded extracellular vesicle-mimetic nanoparticles (MelaNVs) to improve the transdermal delivery of melatonin and to evaluate their therapeutic potential in AD. The MelaNVs were spherical nanoparticles with an average size of 100 nm, which is the optimal size for the transdermal delivery of drugs. MelaNVs showed anti-inflammatory effects by suppressing the release of TNF-α and β-hexosaminidase in LPS-treated RAW264.7 cells and compound 48/80-treated RBL-2H3 cells, respectively. MelaNVs showed a superior suppressive effect compared to an equivalent concentration of free melatonin. Treating a 2,4-dinitrofluorobenzene (DNCB)-induced AD-like mouse model with MelaNVs improved AD by suppressing local inflammation, mast cell infiltration, and fibrosis. In addition, MelaNVs effectively suppressed serum IgE levels and regulated serum IFN-γ and IL-4 levels. Taken together, these results suggest that MelaNVs are novel and efficient transdermal delivery systems of melatonin and that MelaNVs can be used as a treatment to improve AD.

Download Full-text