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 1

Dsg1–/– mice exhibit defects in epidermal adhesion and aberrant expression of adhesion proteins.

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Dsg1–/– mice exhibit defects in epidermal adhesion and aberrant express...
(A) Immunostaining for Dsg1 in E18.5 mouse skin. Dashed line indicates location of the basement membrane. Scale bar = 20 μm (n = 3–5/genotype). (B) Immunoblot for Dsg1 and Dsg3 in protein extracts from E18.5 mouse skin. GAPDH was used as a loading control. (C and D) Quantification of Dsg1 (C) and Dsg3 (D) protein from immunoblots (data represent mean ± SEM, n = 6/genotype). Densitometry values were normalized to the Dsg1+/+ samples and GAPDH. (E) Images of neonates shortly after birth (n = 3–7/genotype). (F) Histochemistry of skin from E18.5 mice. Scale bar = 20 μm (n = 20/genotype). (G) Immunostaining for Dsc1 in E18.5 skin. Dashed line represents basement membrane. Scale bar = 20 μm. (H) Staining intensity of Dsc1 in the epidermis in E18.5 mouse skin (data represent mean ± SEM, n = 5–12/genotype). (I) Volcano plot of upregulated and downregulated genes from RNA-Seq analysis performed on E17.5 skin. FDR ≤ 0.1 and log2 FC ≥ 1 considered significant (n = 4/genotype). (J) Volcano plot of upregulated and downregulated genes from RNA-Seq analysis performed on E18.5 skin (E18.5 data set #1, n = 4/genotype). FDR ≤ 0.1 and log2 FC ≥ 1 considered significant. (K) mRNA expression levels for proteins that make up desmosomes, adherens junctions, and hemidesmosomes from the E17.5 RNA-Seq data set (*FDR < 0.1). (L) mRNA expression levels for proteins that make up desmosomes, adherens junctions, and hemidesmosomes from the E18.5 time course RNA-Seq data set #1 (*FDR < 0.1). Statistical significance for C, D, and H was determined using 1-way ANOVA with a Tukey correction for multiple comparisons.