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

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, 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. 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 two 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. Skin transcriptional profiles from E18.5 wildtype, Dsg1+/-, and Dsg1-/- mice桥粒芯糖蛋白1（Desmoglein 1，Dsg1）是一种仅表达于陆生脊椎动物复层组织的钙粘蛋白，这类组织作为机体关键的物理与免疫屏障发挥功能。人类体内的Dsg1功能丧失突变可引发皮肤损伤、多重过敏，且从患者体内分离的角质形成细胞会表现出促过敏细胞因子表达上调的现象。然而，Dsg1基因缺失引发慢性炎症的具体机制至今尚未明确。为探究Dsg1缺失所触发的系统性应答，本研究对小鼠体内的3个串联型Dsg1基因进行了敲除。对胚胎期Dsg1基因敲除纯合子（Dsg1-/-）小鼠皮肤的全转录组分析显示，在胚胎发育第17.5天（E17.5），其粘附、分化及角质化相关基因的表达出现延迟，其中部分基因的表达在E18.5时得以恢复或上调。对比Dsg1缺陷小鼠与人类的表皮转录组，发现二者存在共同的白细胞介素17（IL-17）偏向性炎症特征。尽管Dsg1-/-小鼠中观察到的细胞间粘附受损情况，与抗Dsg1落叶型天疱疮抗体引发的损伤相似，但天疱疮皮肤损伤的IL-17特征较弱。与该发现的临床意义相符，两名Dsg1缺陷患者接受了原本用于治疗银屑病的白细胞介素12/白细胞介素23（IL-12/IL-23）拮抗剂治疗后，其皮肤损伤得到了改善。综上，除破坏物理屏障外，基因突变导致的Dsg1功能缺失会在胎儿期引发类银屑病炎症特征，且靶向治疗可显著改善患者的皮肤损伤。本数据集包含胚胎第18.5天野生型、Dsg1基因敲除杂合子（Dsg1+/-）及纯合子（Dsg1-/-）小鼠的皮肤转录谱。