TWEAK and Skin Inflammation

摘要 皮肤炎性疾病，如特应性皮炎和牛皮癣，被认为是由相互作用驱动的 免疫系统和表皮或真皮中的结构细胞之间的联系。这些的特点 疾病包括组织重塑，其可以是胶原蛋白和其他细胞外基质的过度沉积， 真皮和/或脂肪层中的基质蛋白、血管损伤、免疫细胞浸润和/或 表皮增生可导致皮肤炎症的原代细胞包括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 这取决于具体的疾病。胶原蛋白和其他细胞外基质蛋白沉积被认为是 主要由成纤维细胞的失调介导，并由炎性细胞分泌的产物驱动， Th 2或Th 17细胞。这些细胞因子，包括IL-13或IL-17，也有助于终末期病理， 特应性皮炎和银屑病，通过直接作用于促进表皮增生， 从角质形成细胞产生另外的可溶性介质如趋化因子。发现新的和 具有类似、交替或协同作用的新蛋白质靶点引起了强烈的兴趣，特别是如果 这些蛋白质在促进特应性皮炎和银屑病的皮肤炎症中是有活性的。我们有 最近表明，一种称为TWEAK（TNFSF 12）的TNF家族蛋白与TNFR超家族相互作用， 当注射到小鼠皮肤中时，分子Fn 14可以促进特应性皮炎和 银屑病，包括真皮和表皮增厚，以及炎性细胞因子的上调， 两种疾病的患者。相应地，TWEAK缺陷的小鼠被强烈地保护免于 在特应性皮炎和银屑病模型中发生皮肤炎症。通过对人体细胞的分析， 发现Fn 14在角质形成细胞和真皮成纤维细胞中表达，初步数据表明， TWEAK可以对这些与皮肤炎症有关的细胞产生强烈的影响。该提案将重点放在体内 特应性皮炎和银屑病的小鼠模型，以及小鼠和人的体外研究 结构细胞参与驱动皮肤炎症，并确定TWEAK如何有助于皮肤 炎症性疾病，描述其细胞和分子靶点，了解TWEAK信号如何 与来自IL-13和IL-17的那些整合，并测试TWEAK和Fn 14是否代表 治疗性地抑制或逆转皮肤炎性疾病。

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.