Skin Barrier Function

T. Agner

• Editorial: S. Karger
• Año: 2016
• ISBN:
  9783318055863
• Categoría: Medizin
• Categoría: Innere Medizin & Diagnose

Although a very fragile structure, the skin barrier is probably one of the most important organs of the body. Inward/out it is responsible for body integrity and outward/in for keeping microbes, chemicals, and allergens from penetrating the skin. Since the role of barrier integrity in atopic dermatitis and the relationship to filaggrin mutations was discovered a decade ago, research focus has been on the skin barrier, and numerous new publications have become available. This book is an interdisciplinary update offering a wide range of information on the subject. It covers new basic research on skin markers, including results on filaggrin and on methods for the assessment of the barrier function. Biological variation and aspects of skin barrier function restoration are discussed as well. Further sections are dedicated to clinical implications of skin barrier integrity, factors influencing the penetration of the skin, influence of wet work, and guidance for prevention and saving the barrier. Distinguished researchers have contributed to this book, providing a comprehensive and thorough overview of the skin barrier function. Researchers in the field, dermatologists, occupational physicians, and related industry will find this publication an essential source of information.

Section I: Basic Parameters

Agner T (ed): Skin Barrier Function.
Curr Probl Dermatol. Basel, Karger, 2016, vol 49, pp 1-7 (DOI: 10.1159/000441539)

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Filaggrin and Skin Barrier Function

Sanja Kezic^a · Ivone Jakasa^b

^aCoronel Institute of Occupational Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ^bLaboratory for Analytical Chemistry, Department of Chemistry and Biochemistry, Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia

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Abstract

The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models of FLG deficiency.

© 2016 S. Karger AG, Basel

Filaggrin and the Skin Barrier

The main physical barrier to excessive water loss and ingress of exogenous chemicals, pathogens and UV radiation resides in the uppermost epidermal layer, the stratum corneum (SC). The SC comprises the corneocytes, flattened skin cells devoid of a nucleus which are surrounded by highly organized lipid lamellar matrix.

The outflow of water from the water-rich epidermis toward the skin surface as well as inflow of substances from outside can occur through intercellular routes along lipid bilayers or through transcellular routes across the corneocytes. The intercellular route is the main diffusional pathway, although the corneocyte route may become relevant for small hydrophilic compounds such as water [1]. The amount of a compound which enters the skin is dependent on its solubility in the SC, which is greatly influenced by the content and relative composition of the lipids and water in the SC. On the other side, the diffusion resistance of the SC, which determines the rate by which a compound diffuses across the SC, is largely dependent on the organization of the lipid bilayers interacting with protein components of the corneocytes [1] and the path length for diffusion, which depends on the thickness of the SC, number of layers of corneocytes, their size and their cohesion [2].

A heightened attention for the role of filaggrin (FLG) in skin barrier function has been underscored by a strong and robust association between loss-of-function mutations in FLG and atopic dermatitis (AD), a common inflammatory skin disease [3]. A skin barrier defect is one of the most distinctive hallmarks of AD. On a population level, approximately 50% of moderate-to-severe AD cases can be attributed to FLG mutations, whereas in the case of mild-to-moderate AD the attributable risk amounts to 15% [3]. In addition to high penetrance, FLG mutations are prevalent in certain populations. Approximately 10% of Northern Europeans from the general population are FLG mutation carriers. The prevalence of FLG mutations in the Asian population varies from 3 to 6%, while the prevalence of FLG mutations in the African population is less than 1% [4].

FLG may affect the skin barrier by multiple mechanisms. As a component of the cornified cell envelope and a filament-aggregating protein, FLG is important for the structural and mechanical integrity of the SC. The degradation products of FLG on the other side are involved in the maintenance of skin hydration and acidic milieu, both crucial for the optimal activity of enzymes involved in skin inflammation, lipid synthesis and desquamation. Recent studies in individuals with ichthyosis vulgaris (IV) with inherited deficiency in FLG and in FLG-null (Flg-/-) mice have indeed confirmed cytoskeletal abnormalities, impaired lamellar body loading, disorganization of the lipid lamellar structure, and altered expression and localization of tight junction proteins [5, 6]. It is obvious that deficiency in FLG can theoretically affect both, solubility properties of the SC as well as diffusion resistance. Over the last decade, a large number of clinical and experimental studies have been undertaken to elucidate the mechanisms by which FLG deficiency affects skin barrier function. In most of these investigations, skin barrier function has been assessed by measuring transepidermal water loss (TEWL). As water, being a small hydrophilic molecule, might not be representative for the penetration of other substances, in various studies percutaneous penetration of hydrophilic and hydrophobic model penetrants have been determined. We review here recent findings on the association between FLG and skin barrier function obtained from clinical studies, and in vitro and animal models of FLG deficiency.

Clinical Studies

The effect of FLG on skin barrier function in vivo in humans has mainly been investigated in clinical studies by comparing TEWL in AD patients with (AD_FLG) and without (AD_non-FLG) loss-of-function mutations in FLG. AD is a common inflammatory skin disease characterized by Th2-mediated immune aberrations and impaired skin barrier function [3]. FLG mutations, which are common in European and Asian populations, are a strong risk factor for the development of AD with the estimated attributable risk in patients with moderate-to-severe AD ranging from 4.2 to 15.1% [3]. The complex interplay of atopic inflammation and FLG makes the assessment of the individual effect of FLG mutations on skin barrier failure in AD difficult. It is well known that the impairment in skin barrier function correlates with the severity of skin inflammation regardless of FLG genotype status [7, 8]. Janssens et al. [8] showed that the organization of lipid bilayers and relative content of very long fatty acid chains in ceramides, both contributing to the skin barrier function, depend on disease severity. Notably, these changes were independent of FLG mutations, but they were correlated with the levels of FLG degradation products, which are important constituents of natural moisturizing factors (NMF) in the SC. FLG mutations are the main determinants of NMF levels in the skin, and wild-type AD patients have reduced NMF levels [9]. A recent study by Cole et al. [10], in which the whole transcriptome has been analyzed by RNA sequencing, revealed two different patterns in AD patients: patients with wild-type FLG showed dysregulation of genes involved in lipid metabolism, while in AD patients with FLG mutations a type 1 interferon-mediated stress response was dominant. Furthermore, the inflammation and Th2-dominant cytokine milieu itself downregulates the expression of FLG, but also affects the composition and organization of SC lipid bilayers [8, 9, 11]. The differences in the disease phenotype of the included AD patients and often underpowered studies might at least partly explain the discrepancies in the effects of FLG mutations regarding skin barrier function reported in the literature. Angelova-Fischer et al. [12] and Jungersted et al. [13] found significantly increased TEWL in the AD patients with FLG mutations (AD_FLG) as compared to the healthy controls. However, no significant differences in the TEWL values bet...