Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor
Lisa M. Godsel, … , Johann E. Gudjonsson, Kathleen J. Green
Lisa M. Godsel, … , Johann E. Gudjonsson, Kathleen J. Green
Published December 14, 2021
Citation Information: J Clin Invest. 2022;132(3):e144363. https://doi.org/10.1172/JCI144363.
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Research Article Dermatology Immunology

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Abstract

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions and multiple allergies, and isolated patient keratinocytes exhibit increased proallergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the 3 tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1–/– skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17–skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1–/– mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of 2 Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, and treatment with a targeted therapy significantly improved skin lesions in patients.

Authors

Lisa M. Godsel, Quinn R. Roth-Carter, Jennifer L. Koetsier, Lam C. Tsoi, Amber L. Huffine, Joshua A. Broussard, Gillian N. Fitz, Sarah M. Lloyd, Junghun Kweon, Hope E. Burks, Marihan Hegazy, Saki Amagai, Paul W. Harms, Xianying Xing, Joseph Kirma, Jodi L. Johnson, Gloria Urciuoli, Lynn T. Doglio, William R. Swindell, Rajeshwar Awatramani, Eli Sprecher, Xiaomin Bao, Eran Cohen-Barak, Caterina Missero, Johann E. Gudjonsson, Kathleen J. Green

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Figure 2

Dsg1 loss interferes with keratinocyte differentiation and epidermal barrier function.

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Dsg1 loss interferes with keratinocyte differentiation and epidermal bar...
(A) Loricrin immunostaining in skin from E18.5 mice. Scale bar = 20 μm (n = 6–13/genotype). (B) Immunoblot for loricrin in protein extracts from E18.5 mouse skin. Actin was used as loading control. (C) Quantification of loricrin protein from immunoblot. Densitometry values were normalized to the Dsg1+/+ samples and actin (data represent mean ± SEM, n = 6/genotype). (D) Gene Ontology (GO) Biological Process terms significantly overrepresented in downregulated genes in E17.5 and E18.5 Dsg1–/– skin and upregulated genes in E18.5 Dsg1–/– skin (E18.5 data set #1). Values in parentheses represent the number of genes associated with each pathway. (E) Normalized counts for barrier- forming genes Dsg4, Dsc1, and Loricrin from E15.5 to E18.5 RNA-Seq data sets (data represent mean ± SEM, *FDR < 0.1). (F) Toluidine blue barrier assays performed on E18.5 embryos demonstrating an outside-in barrier defect in Dsg1–/– animals (4–11/genotype). (G) Transepidermal water loss measured in P1 pups approximately 5 hours after birth (data represent mean ± SEM, 3/genotype). P value calculated using Student’s t test. (H) Quantification of cell circularity in the SG1 layer in epidermal whole mounts from E18.5 mice (data represent mean ± SEM, n = 4–5/genotype). (I) Representative images of phalloidin staining from epidermal whole mounts from E18.5 mice. Scale bar = 20 μm (n = 4–5/genotype). Statistical significance for C and H was determined using 1-way ANOVA with a Tukey correction for multiple comparisons.