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Keratinocytes strike a balance in the epidermal barrier

The epidermis actively maintains its integrity as it is exposed to immunological and physical insults by forming a structural and immune barrier. Keratinocytes in the epidermal barrier must therefore balance the processes of immune defense and immune tolerance. This week in the JCI, work led by Stephen Galli at Stanford University has determined that expression of the E3 ubiquitin ligase RAB guanine nucleotide exchange factor 1 (RABGEF1) in keratinocytes plays a crucial role in maintaining epidermal barrier function. Keratinocyte-specific deletion of RABGEF1 induced an allergic, inflamed phenotype in mice that was associated with abnormal activation of the IL-1R/MYD88/NF-kB signaling pathway. The investigators observed similar abnormalities in RABGEF and MYD88 expression in skin samples from humans with allergic contact dermatitis or atopic dermatitis. Together, these findings indicate that RABGEF1 in keratinocytes targets MYD88 to maintain homeostasis in the epidermal barrier, suggesting that this pathway may be a potential target for treating allergic skin disorders. 

In the accompanying image, fluorescent staining illustrates the structure of the epidermal barrier, showing the arrangement of keratinocytes (DAPI nuclei, cyan), actin (red) and E-cadherin (green). 

Published November 7, 2016, by Elyse Dankoski

Scientific Show Stopper

Related articles

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis
Thomas Marichal, … , Mindy Tsai, Stephen J. Galli
Thomas Marichal, … , Mindy Tsai, Stephen J. Galli
Published December 1, 2016; First published November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4497-4515. https://doi.org/10.1172/JCI86359.
View: Text | PDF
Categories: Research Article Dermatology Immunology

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

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Abstract

Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte-specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-κB signaling pathway and MYD88-dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target.

Authors

Thomas Marichal, Nicolas Gaudenzio, Sophie El Abbas, Riccardo Sibilano, Oliwia Zurek, Philipp Starkl, Laurent L. Reber, Dimitri Pirottin, Jinah Kim, Pierre Chambon, Axel Roers, Nadine Antoine, Yuko Kawakami, Toshiaki Kawakami, Fabrice Bureau, See-Ying Tam, Mindy Tsai, Stephen J. Galli

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