TWEAK and Skin Inflammation

调整和皮肤炎症

基本信息

批准号：
10152528
负责人：
Michael Croft
金额：
$ 38.41万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-18 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152528
关键词：
Acanthosis Adipose tissue Adult Affect Allergens Animal Model Animals Atopic Dermatitis Autoimmune Diseases Automobile Driving Blood Vessels Cell model Cells Cellular Structures Child Clinical Collagen Complement Data Deposition Dermal Dermis Development Disease Disease model Epidermis Extracellular Matrix Proteins Extracellular Protein Feedback Fibroblasts Health Care Costs Human Hyperkeratosis Hyperplasia Immune Immune system Immunity Immunologics In Vitro Individual Infiltration Inflammation Inflammatory Interleukin-13 Interleukin-17 Knockout Mice Knowledge Lead Link Mediating Mediator of activation protein Modeling Molecular Target Mus Myofibroblast Pathogenesis Pathology Pathway interactions Patients Production Protein Family Proteins Psoriasis Recombinants Signal Pathway Signal Transduction Skin Stimulus Subcutaneous Injections Symptoms T-Lymphocyte TNF gene Testing Th2 Cells Therapeutic Therapeutic Intervention Tissues Tumor Necrosis Factor Receptor Up-Regulation cell type cellular targeting chemokine conditional knockout cytokine eosinophil in vitro testing in vivo interest keratinocyte macrophage mast cell member mouse model neutrophil new therapeutic target novel receptor skin disorder synergism therapeutic target

项目摘要

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.

抽象的皮肤炎症性疾病（例如特应性皮炎和牛皮癣）被认为是由相互作用驱动的在表皮或真皮中存在的免疫系统和结构细胞之间。这些功能疾病包括组织重塑，可能过度沉积胶原蛋白和其他细胞外皮肤和/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，具有中性粒细胞，肥大细胞和嗜酸性粒细胞的其他贡献取决于特定疾病。胶原蛋白和其他细胞外基质蛋白沉积被认为主要是由成纤维细胞放松管制的介导的，并由炎症细胞的分泌产物驱动 Th2或Th17细胞。这些包括IL-13或IL-17在内的细胞因子也有助于终末期病理特应性皮炎和牛皮癣，通过促进表皮增生和通过产生其他可溶性介质，例如角质形成细胞的趋化因子。发现新的和执行相似，替代或协同作用的新型蛋白质靶标具有很大的兴趣，尤其是在这些蛋白质可积极促进特应性皮炎和牛皮癣的皮肤炎症。我们有最近显示，与TNFR超家族相互作用的TNF家族蛋白称为Tweak（TNFSF12）分子FN14注射到小鼠的皮肤中时，可以促进特应性皮炎和牛皮癣，包括皮肤和表皮增厚，以及可见的炎性细胞因子的上调在两种疾病的患者中。相应地，不足的调整小鼠受到强烈保护在特应性皮炎和牛皮癣模型中发育炎症。从分析人类细胞，我们已经发现FN14在角质形成细胞和皮肤成纤维细胞中表达，并且初步数据表明调整对这些与皮肤炎症相关的细胞会产生强烈的影响。该建议将重点放在体内特应性皮炎和牛皮癣的小鼠模型，并与小鼠和人的体外研究相辅相成结构细胞涉及驱动皮肤炎症，并确定调整如何有助于皮肤炎症性疾病，描绘其细胞和分子靶标是什么，了解调整信号如何与IL-13和IL-17的元素集成，并测试Tweak和FN14是否代表了新目标治疗抑制或逆转皮肤炎症性疾病。