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Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

ABSTRACT: BACKGROUND:Atopic dermatitis (AD) patients have a barrier disorder in association with Th2 dominant skin inflammation. Galectin-7 (Gal-7), a soluble unglycosylated lectin, is highly expressed in the stratum corneum of AD patients. However, the biological significance of increased Gal-7 expression in AD skin lesions remains unclear. OBJECTIVE:We aimed to investigate the production mechanism and functional role of Gal-7 in AD patients and IL-4/IL-13-stimulated epidermal keratinocytes. METHODS:We assessed the Gal-7 expression levels in skin lesions and sera from AD patients. Gal-7 levels were also measured in monolayered normal human epidermal keratinocytes (NHEKs) and 3-dimensional (3D)-reconstructed epidermis in the presence or absence of IL-4/IL-13 with or without Stat3, Stat6 or Gal-7 gene silencing. RESULTS:Gal-7 was highly expressed in the stratum corneum or intercellular space of AD lesional epidermis as assessed by the stratum corneum proteome analysis and immunohistochemistry. A positive correlation was noted between serum Gal-7 level and transepidermal water loss in patients with AD. These clinical findings were corroborated by our in vitro data, which showed that IL-4/IL-13 facilitated the extracellular release of endogenous Gal-7 in both monolayered NHEKs and 3D-reconstructed epidermis. This machinery was caused by IL-4/IL-13-induced cell damage and inhibited by knockdown of Stat6 but not Stat3 in NHEKs. Moreover, we performed Gal-7 knockdown experiment on 3D-reconstructed epidermis and the result suggested that endogenous Gal-7 serves as a protector from IL-4/IL-13-induced disruption of cell-to-cell adhesion and/or cell-to-extracellular matrix adhesion. CONCLUSION AND CLINICAL RELEVANCE:Our study unveils the characteristic of Gal-7 and its possible role as an alarmin that reflects the IL-4/IL-13-induced skin barrier impairment in AD.

SUBMITTER: Umayahara T

PROVIDER: S-EPMC7496409 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

Umayahara Takatsune T Shimauchi Takatoshi T Iwasaki Manami M Sakabe Jun-Ichi JI Aoshima Masahiro M Nakazawa Shinsuke S Yatagai Tsuyoshi T Yamaguchi Hayato H Phadungsaksawasdi Pawit P Kurihara Kazuo K Tokura Yoshiki Y

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20200614 8

<h4>Background</h4>Atopic dermatitis (AD) patients have a barrier disorder in association with Th2 dominant skin inflammation. Galectin-7 (Gal-7), a soluble unglycosylated lectin, is highly expressed in the stratum corneum of AD patients. However, the biological significance of increased Gal-7 expression in AD skin lesions remains unclear.<h4>Objective</h4>We aimed to investigate the production mechanism and functional role of Gal-7 in AD patients and IL-4/IL-13-stimulated epidermal keratinocyte ...[more]

PMID: 32474952

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Project description:Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

Dataset Information

Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

Publications

Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

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