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

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 7

Critical role of keratinocyte-intrinsic MYD88 in the phenotype of Rabgef1K-KO mice.

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Critical role of keratinocyte-intrinsic MYD88 in the phenotype of Rabgef...
Comparison of Rabgef1/Myd88K-KO and control mice. (A) Specificity and efficiency of Rabgef1 gene deletion assessed by single-cell PCR; numerals indicate the number of cells analyzed for each cell type; results are pooled from 2 sorting experiments. (B) Representative RABGEF1 and MYD88 staining of back skin sections. (C and D) Survival (n = 8–29 mice per group) (C) and body weight (n = 3–6 mice per group) (D) over time. (E) Representative photographs of mice from the indicated genotype at day 49–56 and 1 year after birth. (F) Representative H&E staining of back skin sections. (G) Bars show quantification of dermal and epidermal thickness (n = 5 mice per group). (H and J) Representative confocal microscopy pictures of back skin sections with the indicated staining. (I and K) Bars show protein and mRNA levels of the indicated molecules whose staining is depicted in H and J, as assessed by confocal microscopy and RT-qPCR analyses, respectively (n = 3–4 per group). (B and F) Pictures are representative of 4 or 5 samples per group, each giving similar results. (B, H, and J) Dashed lines identify the dermal-epidermal junction. P values were calculated by Mantel-Cox test (C), 1-way ANOVA (D), 2-way ANOVA with Bonferroni’s test for multiple comparisons (G), and 2-tailed unpaired Student’s t test (I and K). Scale bars: 50 μm; original magnification, ×20 (B and I) or ×63 (J); NS, not significant.