Epithelial barrier repair and prevention of allergy
Elena Goleva, … , Evgeny Berdyshev, Donald Y.M. Leung
Elena Goleva, … , Evgeny Berdyshev, Donald Y.M. Leung
Published February 18, 2019
Citation Information: J Clin Invest. 2019;129(4):1463-1474. https://doi.org/10.1172/JCI124608.
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Review Series

Epithelial barrier repair and prevention of allergy

Abstract

Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention.

Authors

Elena Goleva, Evgeny Berdyshev, Donald Y.M. Leung

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Figure 3

Epidermal differentiation pattern in normal and AD skin.

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Epidermal differentiation pattern in normal and AD skin. (A and B) Epide...
(A and B) Epidermal differentiation pattern in normal (A) and AD (B) skin. The keratinocyte differentiation process is under tight regulation. Cells proliferate in the basal layer of the epidermis. As basal layer keratinocytes detach from the basement membrane and migrate into the first suprabasal layer in the spinous layer, they irreversibly exit the cell cycle and switch from KRT5/KRT14 to KRT1/KRT10 production. During epidermal differentiation, keratinocytes sequentially switch gene expression programs and express the granular layer differentiation markers FLG, LOR, and TGM1. The Wnt/β-catenin pathway is active in the proliferating epidermis, whereas keratinocyte differentiation in the spinous layer is under the control of the Notch pathway. Changes in extracellular Ca2+ and lipid metabolism trigger protein kinase C (PKC) pathway activation and regulate the transcription of FLG, LOR, IVL, and TGM1. In AD skin, abnormalities in the differentiation of keratinocytes result in hyperproliferation of the basal layer, reduction of the spinous layer, and inhibition of markers of terminal differentiation, all of which compromise skin barrier and antimicrobial function.