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 November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4497-4515. https://doi.org/10.1172/JCI86359.
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Research Article Dermatology Immunology Article has an altmetric score of 4

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

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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Figure 2

Epidermal abnormalities and barrier dysfunction in mice with deletion of RABGEF1 in keratinocytes.

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Epidermal abnormalities and barrier dysfunction in mice with deletion of...
(A–E) Comparison of Rabgef1K-KO and control mice. (A) Representative H&E staining of back skin sections. Arrowheads indicate spongiosis. (B and D) Representative confocal microscopy pictures of back skin sections with the indicated staining. (C and E) Bars show protein and mRNA levels of the indicated molecules whose staining is depicted in B and D, as assessed by confocal microscopy and RT-qPCR analyses, respectively (n = 4–6 mice per group). (F) Experimental outline for assessment of epidermal barrier function in tamoxifen-treated Rabgef1KERT2-KO mice. (G) TEWL measurements; results are pooled from 2 independent experiments (n = 6–12 per group). (H) Percentage of dermal DCs containing processed OVA (as assessed by fluorescence in green and red) 30 hours after OVA-DQ skin patching; results are pooled from 3 independent experiments (n = 6–8 per group). (A, B, and D) Pictures are representative of 4 or 5 samples (from 4–5 different mice) per group, each giving similar results. (C, E, G, and H) Results are shown as mean ± SEM, and G and H also show individual values. (A, B, and D) Dashed lines identify the dermal-epidermal junction. P values were calculated by 2-tailed unpaired Student’s t test (C and E) and 1-way ANOVA followed by Tukey’s multiple comparison tests (G and H). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification, ×20 (B) or ×63 (D); TEWL, transepidermal water loss; NS, not significant.