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 6

Differentially expressed genes from Dsg1–/– mice are shared with patients with SAM syndrome to a greater degree than with patients with PF.

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Differentially expressed genes from Dsg1–/– mice are shared with patient...
(A) Overlap between genes upregulated or downregulated in the Dsg1–/– mouse skin (E18.5 data sets #1 and #2), and patients with SAM syndrome or PF. (B) Percentage of genes upregulated in the Dsg1–/– mouse data sets #1 and #2 and patients with SAM syndrome or PF. (C) Predicted transcription factor activity of NFκB1, RELA, and SP1. P values above the x axis represent enrichment of genes targeted by the transcription factor in the upregulated genes, while P values below the x axis represent enrichment of transcription factor targets in the downregulated genes (E18.5 data sets #1 and #2, P < 0.05 considered significant). (D) Overlap between genes upregulated in Dsg1–/– mouse skin (E18.5 data sets #1 and #2) and SAM syndrome. (E) Overlap between genes upregulated in Dsg1–/– mouse skin (E18.5 data sets #1 and #2) and PF. (F) Overlap between genes downregulated in Dsg1–/– mouse skin (E18.5 data sets #1 and #2) and SAM syndrome. (G) Overlap between genes downregulated in Dsg1–/– mouse skin (E18.5 data sets #1 and #2) and PF.