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，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。这些的特点疾病包括组织重塑，这可能是胶原蛋白和其他细胞外物质过度沉积真皮和/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。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，还有中性粒细胞、肥大细胞和嗜酸性粒细胞的额外贡献取决于具体的疾病。胶原蛋白和其他细胞外基质蛋白沉积被认为主要由成纤维细胞失调介导，并由炎症细胞（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学特应性皮炎和牛皮癣，通过直接作用促进表皮增生并通过产生额外的可溶性介质，例如来自角质形成细胞的趋化因子。新的发现和具有相似、替代或协同作用的新蛋白质靶点引起了人们的强烈兴趣，特别是如果这些蛋白质可有效促进特应性皮炎和牛皮癣的皮肤炎症。我们有最近表明，一种名为 TWEAK (TNFSF12) 的 TNF 家族蛋白可与 TNFR 超家族相互作用当将 Fn14 分子注射到小鼠皮肤中时，可以促进特应性皮炎和牛皮癣，包括真皮和表皮增厚，以及炎症细胞因子的上调患有这两种疾病的患者。相应地，TWEAK 缺陷的小鼠受到强有力的保护，免受在特应性皮炎和牛皮癣模型中发生皮肤炎症。通过对人体细胞的分析，我们发现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， TWEAK 可以对这些与皮肤炎症相关的细胞产生强烈的影响。该提案将重点关注体内特应性皮炎和牛皮癣的小鼠模型，辅以小鼠和人类的体外研究与驱动皮肤炎症有关的结构细胞，并确定 TWEAK 如何对皮肤做出贡献炎症性疾病，描述其细胞和分子靶标，了解 TWEAK 信号如何与 IL-13 和 IL-17 的整合，并测试 TWEAK 和 Fn14 是否代表新的目标治疗上抑制或逆转皮肤炎症性疾病。