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.
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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 8

Contribution of global and cell-specific IL-1R expression to the development of ear skin lesions in Rabgef1KERT2-KO mice following topical tamoxifen treatment.

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Contribution of global and cell-specific IL-1R expression to the develop...
(A) Experimental outline for data shown in B–F. (B) Quantification of ear thickness over time. (C and D) Representative photographs of ear pinnae (C) and representative H&E staining of ear pinna sections (D). (E and F) Bars show quantification of epidermal and dermal thickness (E) and inflammatory cell infiltrates in the dermis (F). (G) Experimental outline for data shown in H and I. (H) RT-qPCR analysis of Il1r1 gene expression in peripheral blood mononuclear cells (PBMCs) isolated from the indicated groups of mice. (I) Quantification of ear thickness over time. (J) Representative H&E staining of ear pinna sections. (K and L) Bars show quantification of epidermal and dermal thickness (K) and inflammatory cell infiltrates in the dermis (L). Results are shown as mean ± SEM (as well as individual values in E, F, H, K, and L), and are pooled from 3 independent experiments (n = 6–12 mice per group), each of them giving similar results. (D and J) Dashed lines identify the dermal-epidermal junction. P values were calculated by 2-tailed unpaired Student’s t test (comparison of Il1r1+/+ Rabgef1KERT-KO vs. Il1r1–/– Rabgef1KERT-KO mice) (B); 1-way ANOVA followed by Tukey’s tests for multiple comparisons (E, F, K, and L); or 2-way ANOVA followed by Sidak’s tests for multiple comparisons (I). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; NS, not significant.