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 2

Lamellar body formation and generation of acylceramides and protein-bound ceramides in human epidermis.

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Lamellar body formation and generation of acylceramides and protein-boun...
The enzymes and reactions responsible for creating acylceramides and protein-bound ceramides are shown. The schematics represent acylceramide production, lamellar body assembly and secretion in SG, and formation of the protein-bound ceramides in SC. Acylceramides are formed in the ER and secreted through the Golgi apparatus. ω-OH protein-bound ceramides are formed at the cell membrane. Sequential actions of the fatty acid elongases ELOVL1 and ELOVL4 generate ULCFAs of up to C26 and C28 carbon-chain-lengths, respectively. The cytochrome P450 enzyme CYP4F22 then ω-hydroxylates these ULCFAs, generating ω-OH ULCFAs. Next, the ceramide synthase CERS3 uses ω-OH ULCFAs for ω-OH ceramide synthesis. Finally, the transacylase PNPLA1 forms an ester linkage between the 18:2n-6 fatty acid taken from triglycerides and the ω-OH group of ω-OH ceramide to create an acylceramide. Each enzyme involved in acylceramide production is localized in the ER, indicating that acylceramide production takes place there. Once produced, the UDP-glucose ceramide glucosyltransferase UGCG glycosylates acylceramides in the Golgi apparatus, followed by ABCA12-mediated transport into lamellar bodies. In the course of protein-bound ceramide production, the 18:2n-6 fatty acid portions of acylceramides are subjected to peroxidation by the lipoxygenases ALOX12B and ALOXE3, followed by deglycosylation by β-glucosylceramidase (GBA). Transglutaminase then cross-links the exposed ω-OH group with cornified envelope proteins such as involucrin, envoplakin, and periplakin. Cer, ceramide; GlcCer, glucosylceramide; G, glycosyl group.