Targeting Skin Barrier Function in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. Skin barrier dysfunction is the central abnormality leading to AD. The cause of skin barrier dysfunction is complex and rooted in genetic mutations, interactions between the immune pathway activation and epithelial cells, altered host defense mechanisms, as well as environmental influences that cause epithelial cell activation and release of alarmins (such as thymic stromal lymphopoietin) that can activate the type 2 immune pathway, including generation of interleukins 4 and 13, which induces defects in the skin barrier and increased allergic inflammation. These inflammatory pathways are further influenced by environmental factors including the microbiome (especially Staphylococcus aureus), air pollution, stress, and other factors. As such, AD is a syndrome involving multiple phenotypes, all of which have in common skin barrier dysfunction as a key contributing factor. Understanding mechanisms leading to skin barrier dysfunction in AD is pointing to the development of new topical and systemic treatments in AD that helps keep skin borders secure and effectively treat the disease.

Keywords: Aryl hydrocarbon receptor; Atopic dermatitis; Barrier repair; Dupilumab; Eczema; Interleukin-13; Interleukin-4; Moisturizer; Staphylococcus aureus.

FIGURE 1.

The multifaceted skin barrier. (A) Epidermal barrier maintenance and repair starts skin deep in the stratum basale as basal keratinocytes proliferate under cues of master regulating transcription factors (p63, NOTCH) and signal transduction pathways (WNT, YAP) and exit the cell cycle, becoming early differentiated keratinocytes in the stratum spinosum. (B) After transitioning from the stratum spinosum to the granulosum, the characteristic keratohyalin granules (KGs) become apparent, holding the pro-filaggrin (FLG) protein that will be proteolytically processed into FLG monomers and later further deaminated into free amino acids that form the NMF. (C) Production of NMF from FLG protein is essential for stratum corneum hydration, and NMF levels correlate to barrier function parameters like TEWL. (D) The formation of the acid mantle is part of the chemical barrier next to the secretion of AMPs and terminal differentiation proteinederived cationic intrinsically disordered antimicrobial peptides (CIDAMPs), including FLG, hornerin (HRNR), and late cornified envelope (LCE) proteins. (E) Upon terminal differentiation in the last living cell layer, cell organelles are degraded, leaving only tightly crosslinked cornified envelopes (CEs) embedded in lipid matrix that form the stratum corneum and provide the physical barrier that withholds passive permeation of allergens and pathogens. (F) The commensal microbiota of the skin microbiome provides an important microbial barrier against pathogens by competition for skin surface, nutrients, and production of bactericidins. The commensal microbial metabolites feed back to the host and tune skin barrier formation by activation of host receptors, like the AHR. The AHR is involved in almost all processes that relate to skin barrier formation and function.

FIGURE 2.

Example of optical coherence tomography (OCT) images taken from the forearm of healthy skin and skin affected to different degrees by atopic dermatitis (AD) using the Vivosight OCT machine (Michelson Diagnostic, Maidstone, UK). (Top row) The raw images. (Bottom row) The same images have been segmented to highlight the changing structure of the skin. (Images provided by Dr. Robert Byers, Sheffield Dermatology Research, The University of Sheffield, Sheffield, UK.)

FIGURE 3.

Nine (22 to 62 year old; seven females and two males) nonatopic human volunteers were enrolled in this study. Creams (n = 3 to 4 subjects each) were applied to 3×3 cm² areas (of previously untreated skin sites) on the flexural surface of the forearm twice daily for 4 days. Two sites, 12–14 cm apart, were selected on each forearm. Untreated sites on contralateral forearms served as normal controls. During the study period, no detergents or skin care products were applied to the forearm flexors. On day 5, basal pH, hydration, and transepidermal water loss were measured with a Tewameter (Evalulab, Montreal, Canada). Barrier recovery rates were assessed 3 hours following barrier disruption by repeated tape stripping until transepidermal water loss levels ≥5 mg/cm²/h. Data are expressed as mean ± standard error of the mean. SB, styrene butadiene. Reprinted with permission from Elias et al.)