Galectin-3 in regulation of allergic skin inflammation

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。这是一个重大的医疗问题，在工业化国家，多达15-20%的儿童受到这种疾病的影响。治疗特应性皮炎仍然是一个挑战。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起重要作用。该提案旨在建立集素家族成员在特应性皮炎中的作用，并长期目标是开发一种治疗这种疾病的新疗法。半乳糖凝集素-3是动物凝集素家族的成员，由它们对2-半乳糖苷的亲和力和一致的序列定义。它由多种细胞类型表达，包括上皮细胞和各种白细胞。使用外源性半乳糖凝集素-3已经证明了许多细胞外功能，这些功能与它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多种细胞功能。通过研究半乳糖凝集素-3缺陷小鼠的T细胞，我们已经证明半乳糖凝集素-3是Th1细胞的抑制调节剂，并通过促进TCR下调来抑制T细胞受体（TCR）介导的Th1反应。半乳糖凝集素-3在TCR激活的T细胞中定位于细胞内的免疫突触。我们也证明了半乳糖凝集素-3抑制树突状细胞产生IL-12。此外，我们已经证明了半乳糖凝集素-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是一种半乳糖凝集素-3结合伙伴，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。我们也有其他信息表明半乳糖凝集素-3与MVBs和外泌体有关。在特应性皮炎的小鼠模型中，我们发现半乳糖凝集素-3促进Th2反应并抑制Th1反应，这部分是通过蛋白质在T细胞和树突状细胞中的功能实现的。在本提案中，我们计划验证半乳糖凝集素-3通过在IS中发挥作用来抑制tcr介导的Th1反应的假设；2)通过抑制IL-12的产生对树突状细胞的抗原呈递功能至关重要，并作为外泌体相关蛋白发挥作用；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。

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).