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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

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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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Figure 3

Type 2 cutaneous inflammation and elevated serum IgE in adult Rabgef1K-KO mice.

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Type 2 cutaneous inflammation and elevated serum IgE in adult Rabgef1K-K...
(A–H) Rabgef1K-KO and control mice are compared. (A) Representative TSLP staining of back skin sections. (B) Assessment of dermal MCs by toluidine blue (left panel) or avidin staining (right panel) (82). (C) Representative H&E staining of back skin sections (different areas of the sections in Figure 2A); arrows indicate eosinophils. (D) Representative dot plot of dermal CD45+ leukocytes, CD4+ T cells, SSChi eosinophils (also positive for SiglecF), and Ly6G(Gr-1)+CD11b+ neutrophils; bar graphs show quantification of the percentage of cells (n = 6–8 per group). (E) Representative pictures of skin-draining lymph nodes (DLNs); bar graphs show quantification of LN cell numbers (n = 8–20 mice per group). (F and G) Assessment of IgE levels in the serum (n = 4–10 mice per group) (F) and on the surface of blood basophils (G); bar graph in G shows quantification of the percentage increase in mean fluorescence intensity (MFI) versus control mice (n = 4–10 per group). (H) RT-qPCR analysis of the selected genes (n = 3 mice per group). (I) Experimental outline. (J) Representative dot plots depicting intracellular protein expression of GATA-3, T-bet, Foxp3, and ROR-γt within living CD4+ T cells. Insets show percentage of cells in the gated subpopulation. (K) Bars show quantification of the numbers of CD4+ T cell subsets in the dermis of the ear pinnae (left) and in the DLN (right) (n = 5–6 mice per group, 2 independent experiments). (A–C) Pictures are representative of 4 or 5 samples per group, each giving similar results. (D–H and K) Results are shown as mean ± SEM, and F, G, and K also show individual values. (A–C) Dashed lines identify the dermal-epidermal junction. P values were calculated by 2-tailed unpaired Student’s t test (E–G) and 2-way ANOVA followed by Bonferroni’s test for multiple comparisons (H and K). **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification in A and B, ×20; NS, not significant.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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