TWEAK and Skin Inflammation

摘要 皮肤炎症性疾病，如特应性皮炎和牛皮癣，被认为是由这种相互作用引起的。 在免疫系统和存在于表皮或真皮中的结构细胞之间。这些产品的特点 疾病包括组织重塑，这可能是胶原和其他细胞外过度沉积 真皮和/或脂肪层中的基质蛋白、血管损伤、免疫细胞渗透和/或 表皮增生症。可能导致皮肤炎症的主要细胞包括T细胞、成纤维细胞、 角质形成细胞和巨噬细胞，另外还有中性粒细胞、肥大细胞和嗜酸性粒细胞 取决于具体的疾病。胶原蛋白和其他细胞外基质蛋白沉积被认为 主要通过放松对成纤维细胞的调节，并由炎症细胞的分泌产物驱动，如 Th2或Th17细胞。这些细胞因子，包括IL-13或IL-17，也有助于终末期病理。 特应性皮炎和牛皮癣，通过直接促进表皮增生和通过 角质形成细胞产生额外的可溶性介质，如趋化因子。新的和新的发现 人们对执行相似、交替或协同作用的新型蛋白质靶点非常感兴趣，特别是如果 这些蛋白质在促进特应性皮炎和牛皮癣的皮肤炎症方面很活跃。我们有 最近发现一种名为TWEEP(TNFSF12)的肿瘤坏死因子家族蛋白，它与TNFR超家族相互作用 当Fn14分子注射到小鼠皮肤中时，可以促进特应性皮炎和 银屑病，包括真皮和表皮增厚，以及炎症细胞因子的上调 在患有这两种疾病的患者中。相应地，缺乏调整能力的小鼠会受到强烈的保护 在特应性皮炎和牛皮癣模型中发生皮肤炎症。从对人类细胞的分析来看，我们 已经发现Fn14在角质形成细胞和真皮成纤维细胞中表达，初步数据表明 微调可以对这些与皮肤炎症有关的细胞产生强烈的影响。这项提案将重点放在体内 特应性皮炎和银屑病的小鼠模型，辅之以小鼠和人的体外研究 结构细胞参与了皮肤炎症的驱动，并决定了微调对皮肤的影响 炎症性疾病，描述其细胞和分子靶点是什么，了解如何调整信号 与IL-13和IL-17中的IL-13和IL-17集成，并测试TWEE和Fn14是否代表 在治疗上抑制或逆转皮肤炎症性疾病。

ABSTRACT Skin inflammatory diseases, such as atopic dermatitis and psoriasis, are thought to be driven by the interplay between the immune system and structural cells present in the epidermis or dermis. Features of these diseases include tissue remodeling which can be excessive deposition of collagen and other extracellular matrix proteins in the dermal and/or adipose layers, vascular damage, immune cell infiltration, and/or epidermal hyperplasia. Primary cells that can contribute to skin inflammation include T cells, fibroblasts, keratinocytes, and macrophages, with additional contributions of neutrophils, mast cells, and eosinophils depending on the specific disease. Collagen and other extracellular matrix protein deposition is thought mediated primarily by deregulation of fibroblasts, and driven by secreted products from inflammatory cells like Th2 or Th17 cells. These cytokines, which include IL-13 or IL-17, also contribute to end-stage pathology in atopic dermatitis and psoriasis, through direct actions in promoting epidermal hyperplasia and through production of additional soluble mediators such as chemokines from keratinocytes. The discovery of new and novel protein targets that perform similar, alternate, or synergistic actions is of strong interest, especially if these proteins are active in promoting skin inflammation in both atopic dermatitis and psoriasis. We have recently shown that a TNF family protein, called TWEAK (TNFSF12), that interacts with the TNFR superfamily molecule Fn14, when injected into the skin of mice, can promote features of both atopic dermatitis and psoriasis, including dermal and epidermal thickening, and upregulation of inflammatory cytokines that are seen in patients with both diseases. Correspondingly, mice that are deficient in TWEAK are strongly protected from developing skin inflammation in models of atopic dermatitis and psoriasis. From analysis of human cells, we have found that Fn14 is expressed in keratinocytes and dermal fibroblasts, and preliminary data suggests that TWEAK can have strong effects on these cells linked to skin inflammation. This proposal will focus on in vivo mouse models of atopic dermatitis and psoriasis, complemented with in vitro studies of mouse and human structural cells implicated in driving skin inflammation, and determine how TWEAK contributes to skin inflammatory disease, delineate what are its cellular and molecular targets, understand how TWEAK signals integrate with those from IL-13 and IL-17, and test whether TWEAK and Fn14 represent new targets for therapeutically dampening or reversing skin inflammatory disease.