Galectin-3 in regulation of allergic skin inflammation

Galectin-3 调节过敏性皮肤炎症

• 批准号: 7785910
• 负责人: FU-TONG LIU
• 金额: $ 35.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785910
• 关键词: Affect; Affinity; Allergic; Amino Acid Sequence; Animal Lectins; Antigens; Area; Atopic Dermatitis; Binding; Biogenesis; Biological Process; Carbohydrates; Cell Surface Proteins; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Child; Chronic; Complex; Consensus; Consensus Sequence; Data; Dendritic Cells; Developed Countries; Development; Disease; Epithelial Cells; Family; Galactose Binding Lectin; Galactosides; Galectin 3; Genetically Engineered Mouse; Goals; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Lectin; Leukocytes; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Multivesicular Body; Mus; Peptide Signal Sequences; Play; Polysaccharides; Population; Prevalence; Process; Production; Proteins; Regulation; Role; Screening procedure; Skin; Sorting - Cell Movement; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Vesicle; Work; Yeasts; allergic airway inflammation; base; carbohydrate receptor; cell type; crosslink; cytokine; extracellular; immunological synapse; in vivo; mast cell; member; mouse model; novel; novel therapeutics; protein function; public health relevance; receptor downregulation; receptor expression; response; skin disorder; yeast two hybrid system

DESCRIPTION (provided by applicant): Atopic dermatitis is a common chronic inflammatory skin disease. It is a significant medical problem and as much as 15-20% of children are affected by this disease in industrialized countries. Treatment of atopic dermatitis continues to be a challenge. The current model suggests that atopic dermatitis is attributable to a Th2-mediated inflammatory response and T cells, dendritic cells, and mast cells play important roles. This proposal aims at the establishment of the role of a member of the galectin family in atopic dermatitis with the long-term goal of developing a novel therapy for treatment of this disease. Galectin-3 is a member of a family of animal lectins defined by their affinity for 2-galactosides and consensus sequences. It is expressed by a number of cell types, including epithelial cells and various leukocytes. A number of extracellular functions have been demonstrated by using exogenously added galectin-3 and these are associated with its binding to and crosslinking cell surface glycans. However, there is a great deal of evidence that endogenous galectin-3 regulates various cellular functions through intracellular actions. By studying T cells from galectin-3-deficient mice, we have demonstrated that galectin-3 is an inhibitory regulator in Th1 cells and suppresses the T cell receptor (TCR)-mediated Th1 response by promoting TCR downregulation. Galectin-3 is localized intracellularly at the immunological synapse in T cells activated by TCR engagement. We have also demonstrated that galectin-3 suppresses the production of IL-12 by dendritic cells. In addition, we have demonstrated an important role of galectin-3 in mast cells. By yeast two-hybrid screening, we found Alix as a galectin-3-binding partner, which is known to be a component of the endosomal sorting complex required for transport (ESCRT) and the multivesicular body (MVB). We also have other information suggesting that galectin-3 is associated with MVBs and exosomes. In a mouse model of atopic dermatitis, we found that galectin-3 promotes the Th2 response and suppresses the Th1 response and this is in part through the protein's function in T cells and dendritic cells. In this proposal, we plan to test the hypothesis that galectin-3 1) suppresses the TCR-mediated Th1 response by functioning at the IS; 2) is critical for the antigen-presenting function of dendritic cells by suppressing IL-12 production and functions as an exosome-associated protein; 3) promotes allergic skin inflammation through dendritic cells and mast cells (in addition to T cells). PUBLIC HEALTH RELEVANCE: Atopic dermatitis is a common chronic inflammatory skin disease. The prevalence of this disease has increased by two- to three-fold during the past three decades in industrialized countries, where the current prevalence in children is estimated to be 15-20%. The treatment of this disease continues to be a challenge. Elucidation of the cellular and molecular bases of this disease is important for development of novel therapeutic strategies. Galectin-3 is a member of a family of proteins that bind carbohydrates, called lectins. The galectin family defined by their binding of 2-galactosides and sharing of similar amino acid sequences. When galectin-3 is added to various cells, it can bind to cell surface proteins that have attached carbohydrates recognizable by the lectin. However, there is a great deal of evidence that galectin-3 that is present inside the cells regulates various cellular functions through intracellular actions (without the protein being secreted). We have obtained important information on the functions of galectin-3 by studying genetically engineered mice we generated that lack galectin-3. Most recently, we found that galectin-3 plays an important function in the response of T cells. We found that galectin-3 is clustered inside the cells in the area that is important for the T cell response called the immunological synapse. We also found that galectin-3 has an important function in another cell type called dendritic cells. We have previously demonstrated that galectin-3 promotes allergic airway inflammation. We now have a significant amount of data supporting the role of this protein in a mouse model of atopic dermatitis. Additional work is required for understanding how galectin-3 regulates these inflammatory processes and for advancing strategies for developing galectin-3-targeting therapies. In this proposal, we plan to establish the mechanism by which galectin-3 regulates the responses of T cell and dendritic cell, which are both key cell types in the development of allergic skin inflammation associated with atopic dermatitis. We also plan to elucidate the cellular basis for galectin-3's regulatory role in a mouse model of atopic dermatitis.

描述（申请人提供）：特应性皮炎是一种常见的慢性炎症性皮肤病。这是一个严重的医疗问题，在工业化国家，多达 15-20% 的儿童受到这种疾病的影响。特应性皮炎的治疗仍然是一个挑战。目前的模型表明，特应性皮炎可归因于 Th2 介导的炎症反应，T 细胞、树突状细胞和肥大细胞发挥着重要作用。该提案旨在确定半乳糖凝集素家族成员在特应性皮炎中的作用，长期目标是开发一种治疗该疾病的新疗法。 Galectin-3 是动物凝集素家族的一员，其定义是其对 2-半乳糖苷和共有序列的亲和力。它由多种细胞类型表达，包括上皮细胞和各种白细胞。通过使用外源添加的半乳糖凝集素 3 已证明了许多细胞外功能，这些功能与其与细胞表面聚糖的结合和交联有关。然而，有大量证据表明内源性半乳糖凝集素3通过细胞内作用调节各种细胞功能。通过研究半乳糖凝集素 3 缺陷小鼠的 T 细胞，我们证明半乳糖凝集素 3 是 Th1 细胞的抑制性调节因子，通过促进 TCR 下调来抑制 T 细胞受体 (TCR) 介导的 Th1 反应。 Galectin-3 位于 T 细胞的细胞内免疫突触处，由 TCR 结合激活。我们还证明，galectin-3 可以抑制树突状细胞产生 IL-12。此外，我们还证明了 galectin-3 在肥大细胞中的重要作用。通过酵母双杂交筛选，我们发现 Alix 作为半乳糖凝集素 3 结合伴侣，已知它是运输 (ESCRT) 和多泡体 (MVB) 所需的内体分选复合体的组成部分。我们还有其他信息表明 galectin-3 与 MVB 和外泌体相关。在特应性皮炎小鼠模型中，我们发现 galectin-3 促进 Th2 反应并抑制 Th1 反应，这部分是通过该蛋白在 T 细胞和树突状细胞中的功能实现的。在本提案中，我们计划检验以下假设：galectin-3 1) 通过在 IS 上发挥作用来抑制 TCR 介导的 Th1 反应； 2) 通过抑制 IL-12 的产生和作为外泌体相关蛋白的功能，对树突状细胞的抗原呈递功能至关重要； 3）通过树突状细胞和肥大细胞（除了T细胞）促进过敏性皮肤炎症。 公共卫生相关性：特应性皮炎是一种常见的慢性炎症性皮肤病。在过去三十年中，这种疾病的患病率在工业化国家增加了两到三倍，目前儿童患病率估计为 15-20%。这种疾病的治疗仍然是一个挑战。阐明这种疾病的细胞和分子基础对于开发新的治疗策略非常重要。 Galectin-3 是结合碳水化合物的蛋白质家族（称为凝集素）的成员。半乳糖凝集素家族由 2-半乳糖苷的结合和共享相似的氨基酸序列定义。当半乳糖凝集素 3 添加到各种细胞中时，它可以与细胞表面蛋白结合，这些蛋白附着有可被凝集素识别的碳水化合物。然而，有大量证据表明细胞内存在的半乳糖凝集素-3 通过细胞内作用（不分泌蛋白质）调节各种细胞功能。 通过研究我们培育的缺乏半乳糖凝集素 3 的基因工程小鼠，我们获得了有关半乳糖凝集素 3 功能的重要信息。最近，我们发现半乳糖凝集素-3 在 T 细胞的反应中发挥着重要作用。我们发现，galectin-3 聚集在细胞内对 T 细胞反应很重要的区域（称为免疫突触）。我们还发现，galectin-3 在另一种称为树突状细胞的细胞类型中具有重要功能。 我们之前已经证明半乳糖凝集素 3 会促进过敏性气道炎症。我们现在有大量数据支持这种蛋白质在特应性皮炎小鼠模型中的作用。需要开展更多工作来了解 galectin-3 如何调节这些炎症过程，并推进开发 galectin-3 靶向疗法的策略。 在本提案中，我们计划建立半乳糖凝集素 3 调节 T 细胞和树突状细胞反应的机制，这两种细胞都是与特应性皮炎相关的过敏性皮肤炎症发展的关键细胞类型。我们还计划阐明 galectin-3 在特应性皮炎小鼠模型中调节作用的细胞基础。