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

Abstract

AbstractDesmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1’s importance in epidermal integrity is underscored by genetic, autoimmune and bacterial toxin-mediated disorders interfering with Dsg1 function. Dsg1 loss-of-function mutations in humans result not only in skin lesions, but also multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic 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 three tandem Dsg1 genes in mice using CRISPR/Cas9. Whole transcriptome analysis of E18.5 Dsg1−/− skin showed changes consistent with the observed aberrant differentiation and barrier impairment. Comparing epidermal transcriptomes from E18.5 Dsg1-deficient mice and humans with Dsg1 mutations revealed a shared psoriatic-like IL-17-skewed inflammatory signature and less so a pro-allergic IL-4/13 signature. Although the impaired intercellular adhesion observed in Dsg1−/− mice resembles that resulting from autoimmune anti-Dsg1 pemphigus foliaceus antibodies, transcriptomic analysis of pemphigus skin lesions lacks a prominent IL-17 signature. Thus, beyond impairing the physical barrier, chronic loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, possibly predisposing to skin inflammation.