Epithelial barrier repair and prevention of allergy

Abstract

Allergic diseases such as atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis affect more than 30% of the population (1-3). These diseases have in common a dysfunctional epithelial barrier, resulting in the penetration of allergens and microbes, accompanied by the release of epithelial-derived cytokines (e.g., thymic stromal lymphopoietin [TSLP], IL-25, IL-33), which drive type 2 immune responses. Although other immune pathways can modify the course of illness, cytokines including IL-4, IL-13, IL-31, TSLP, and IL-33 play a key role in allergic diseases (4-8), eliciting local tissue injury and repair (5,(9)(10)(11)(12)(13)(14).AD is the most prevalent chronic inflammatory skin disease (3,(15)(16)(17)(18)(19). In a subset of allergic patients, it is thought that ADrelated skin epithelial dysfunction contributes to the atopic march, which starts with AD and often leads directly to FA (20-23). The link from AD to respiratory allergy is more controversial; however, atopic march progression is facilitated in patients who develop IgE to both food and inhalant allergens (24).In this Review, we describe formation of the skin barrier, review the link between altered skin barrier formation and AD, discuss evidence for epithelial barrier dysfunction in other allergic diseases, and explore epithelial barrier intervention/repair strategies with the goal of preventing AD and the atopic march. The cornified envelope and keratinocyte differentiation in the skinThe skin's barrier function primarily depends on the outermost epidermal layer, stratum corneum (SC). To form SC, keratinocytes pass through a tightly regulated differentiation program and sequentially form stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and SC layers of the skin (Figure 1). In human skin, keratinocytes irreversibly exit the cell cycle after mitosis in the basal layer and differentiate progressively across the epidermis toward the SC. Each layer is defined by its expression of characteristic morphological and biochemical features indicating its state of differentiation (25-27). The keratins KRT5 and KRT14 are predominantly expressed by basal keratinocytes. The markers of early differentiation KRT1 and KRT10 are made in SS. The cornified envelope precursors involucrin (IVL) and transglutaminase-1 (TGM1) are also present in SS. Late differentiation markers including the cornified envelope protein loricrin (LOR) and the precursor of the keratin cross-linking protein filaggrin (FLG) are expressed in SG keratinocytes. TGM1 cross-links IVL, LOR, and other structural proteins to form the cornified envelope.Calcium forms a steep gradient across the human epidermis, increasing from the SB (5 μM) to the outer SG (>20 μM) (27, 28). Importantly, there is cell-to-cell heterogeneity in average Ca 2+ concentrations in the epidermis (28). Formation of the Ca 2+ gradient coincides with key developmental milestones of skin barrier formation and differentiation into the SC.Primary human keratinocyte cultures are an excellent model for...

Recent developments and highlights in food allergy

“…Consequently, epithelial dysregulation and mutations or polymorphisms of genes important for skin barrier, such as filaggrin, SPINK5, 1 and SERPINB7, have been linked to eczema development and also food allergy. [2][3][4][5][6] Recently, electrical impedance spectroscopy has shown promising results in rodents to measure skin barrier function. This is of relevance since it can be easily adapted for usage on humans.…”

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

“…The skin barrier prevents excessive water loss, as well as the entry of microorganisms, allergens, and chemical substances. Dysfunction of the skin barrier causes infectious diseases and skin disorders such as atopic dermatitis and ichthyosis (1)(2)(3). Skin consists of the epidermis, dermis, and subcutaneous tissue.…”

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“…Patients with chronic asthma continuously display chronic inflammation and oxidative stress [8]. Furthermore, pulmonary epithelial cells and immune cells are continuously activated, and they release various inflammatory cytokines, inflammatory mediators, and oxidative molecules that damage cells and tissues, which reduces lung function [6,29]. Previous studies have shown that some natural products could reduce airway inflammation in asthmatic mice [30,31].…”