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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.
Highlights
The multi-layered epidermal barrier is made up of interdependent microbiome, chemical, physical, and immune components
In addition to its roles in harnessing Erk signaling, we showed that Dsg[1] remodels the cortical actin cytoskeleton to temporarily reduce tension in basal cells, which is necessary for promoting stratification in human epidermal organotypic cultures (21)
The functional differences among these three genes in various tissues are not well understood (25). qRT-PCR of Desmoglein 1 (Dsg1)+/+ mouse tissue revealed that only Dsg1a and b genes are expressed in skin, as well as the esophagus, tongue and forestomach, while Dsg1c expression was found only in the liver (Supplemental Figure 1A)
Summary
The multi-layered epidermal barrier is made up of interdependent microbiome, chemical, physical, and immune components. These components work together to protect against water loss, physical insults, and infection (1, 2). In multi-layered epithelia such as the epidermis, architectural features are polarized along the entire apical to basal axis of the stratified epithelium. Among the most polarized molecules in the epidermis are desmosomal cadherins, desmogleins (Dsgs), and desmocollins (Dscs) (4, 5). These transmembrane cell-cell adhesion molecules cooperate with plakins and armadillo proteins to anchor intermediate filaments (IF) to the desmosome, providing tissues with tensile strength. Bacterial toxins, pemphigus autoimmune antibodies, and dysregulated expression of these cadherins cause a range of mild to potentially lethal disorders including keratodermas, blistering diseases, and cancer in humans and mouse models (5-9)
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