Neuroinflammation-induced lymphangiogenesis in the CNS

中枢神经系统中神经炎症诱导的淋巴管生成

• 批准号: 10224352
• 负责人: Zsuzsanna Fabry
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224352
• 关键词: Alzheimer' s Disease; Antibodies; Antigen-Presenting Cells; Antigens; Area; Astrocytes; Autoimmunity; Automobile Driving; Biological; Brain; CD44 Antigens; CNS autoimmunity; Cells; Central Nervous System Diseases; Cervical lymph node group; Characteristics; Clinical; Data; Dendritic Cells; Development; Disease; Drainage procedure; Dura Mater; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Fluid Balance; Functional disorder; Gene Expression Profile; Glial Fibrillary Acidic Protein; Heterogeneity; ITGAX gene; Immune; Immunohistochemistry; In Situ; Inflammatory; Ligands; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphedema; Lymphoid; Lymphoid Cell; Mediating; Multiple Sclerosis; Mus; Myeloid Progenitor Cells; Neurons; Oligodendroglia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmacology; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Regulatory Pathway; Reporter; Role; Sculpture; Source; Spinal Cord; Stroke; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; Tyrosine Kinase Inhibitor; VEGFC gene; Vascular Endothelial Growth Factor Receptor-3; Work; adaptive immunity; cribriform plate; draining lymph node; in vivo imaging; inflammatory milieu; lymph nodes; lymphatic vessel; macrophage; monocyte; mouse model; nestin protein; neuroinflammation; podoplanin; recruit; targeted treatment; testing access; transcription factor

PROJECT SUMMARY/ABSTRACT Adaptive immunity in most tissues of the body involves the drainage of antigens or antigen presenting cells within conventional lymphatic vessels to the draining lymph nodes where antigen is presented to T cells. However, there are no conventional lymphatic vessels within the CNS parenchyma. Alternatively, it has been hypothesized that antigens, antigen presenting cells, and CSF may drain from the CNS into lymphatics near the cribriform plate or dura to maintain fluid homeostasis and antigen drainage during steady-state conditions, yet little is known about the role of these lymphatic vessels during neuroinflammation. We discovered that lymphatic vessels near the cribriform plate undergo extensive in situ neo-lymphangiogenesis during experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis. Our preliminary data show that these neo-lymphatic vessels near the cribriform plate are functionally able to drain both CSF and cells that were once in the CNS parenchyma. We further found the during EAE, VEGFC protein is produced by infiltrating macrophages and dendritic cells to promote VEGFR3 dependent neo-lymphangiogenesis near the cribriform plate. These data are the first to describe neo-lymphangiogenesis near the cribriform plate during neuroinflammation. The long-term objective of this project is to characterize the functionality and contribution of newly formed lymphoid vessels near to the cribriform plate to autoimmunity and stroke of the CNS. The specific objectives of this proposal are (1) to define the characteristics and regulatory mechanisms driving neo-lymphangiogenesis near the cribriform plate (Aim 1); (2) to test the functionality of neo-lymphatic vessels near the cribriform plate and compare them to different CNS area lymphatics (Aim 2); and (3) to understand the translational value of exacerbating or inhibiting neo-lymphangiogenesis near the cribriform plate in order to treat CNS diseases (Aim 3). Pharmacological inhibition or exacerbation of neo-lymphangiogensis to modulate pathology in CNS diseases may have potential therapeutic values for CNS autoimmunity and ischemic trauma.

项目摘要/摘要 体内大多数组织中的获得性免疫包括排出体内的抗原或抗原提呈细胞 传统的淋巴管通向引流的淋巴结，抗原被提呈给T细胞。然而， 中枢神经系统实质内无常规淋巴管。或者，它是被假设的 这些抗原、抗原提呈细胞和脑脊液可能从中枢神经系统流入筛骨附近的淋巴管。 平板或硬脑膜在稳态条件下维持液体平衡和抗原排出，但知之甚少。 关于这些淋巴管在神经炎症中的作用。 我们发现筛板附近的淋巴管经历了广泛的原位新生淋巴管生成。 在实验性自身免疫性脑脊髓炎(EAE)期间，建立多发性硬化症的小鼠模型。我们的预赛 数据显示，筛板附近的这些新淋巴管在功能上能够排出脑脊液和脑脊液 曾经在中枢神经系统实质中的细胞。我们进一步发现，在EAE过程中，VEGFC蛋白是由 侵袭巨噬细胞和树突状细胞促进血管内皮生长因子受体3依赖的新淋巴管生成 筛板。这些数据首次描述了筛板附近的新生淋巴管生成。 神经炎。该项目的长期目标是确定功能和贡献的特征 筛板附近新形成的淋巴管与自身免疫和中枢神经系统卒中有关。 这项提案的具体目标是(1)界定驱动程序的特征和监管机制 筛板附近的新淋巴管生成(目标1)；(2)测试新淋巴管的功能 并与不同的中枢神经系统区域的淋巴管进行比较(目标2)；以及(3)了解 加重或抑制筛板附近新生淋巴管生成对治疗的意义 中枢神经系统疾病(目标3)。 药物抑制或加重新生淋巴管生成以调节中枢神经系统疾病的病理 可能对中枢神经系统自身免疫和缺血性损伤有潜在的治疗价值。