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

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

×

Figure 1

Role of keratinocyte-intrinsic Rabgef1 in health and skin homeostasis.

Options: View larger image (or click on image) Download as PowerPoint
Role of keratinocyte-intrinsic Rabgef1 in health and skin homeostasis. (...
(A) Specificity and efficiency of Cre-mediated Rabgef1 deletion assessed by single-cell PCR; numerals indicate the number of single cells analyzed, and results are pooled from 2 separate experiments. (B–G) Comparison between Rabgef1K-KO and control mice. (B) Representative RABGEF1 staining of back skin sections from adult mice. (C) Survival (n = 9 and 29, respectively) and (D) body weight (n = 8 and 18, respectively) over time in Rabgef1K-KO and control mice. (E) Representative photographs at day 1–2, day 7–9, and day 49–56 after birth. (F) Representative H&E staining of back skin sections. (G) Bars show quantification of dermal and epidermal thickness (n = 5–7 mice per group). (H) Experimental outline for tamoxifen-induced Rabgef1 deletion in Rabgef1KERT2-KO mice. (I–L) Comparison between tamoxifen-treated Rabgef1fl/fl and Rabgef1KERT2-KO mice. Representative H&E staining (I) and RABGEF1 staining (J) of back skin sections. (K) Bars show quantification of dermal and epidermal thickness (n = 7–8 mice per group, 2 independent experiments). (L) Bacterial CFU counts per cm2 of skin area (n = 9–12 per group, 3 independent experiments). (B, E, F, and I) Pictures are representative of more than 5 samples analyzed per group, and (I and J) 3 independent experiments, each giving similar results. (G, K, and L) Data shown are mean ± SEM, as well as individual values. (B, F, I, 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 K), or Mann-Whitney test (L). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification in B and I, ×20; NS, not significant.