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.

项目总结/摘要 在身体的大多数组织中的适应性免疫涉及抗原或抗原呈递细胞内的引流。 传统淋巴管到引流淋巴结，在那里抗原被提呈给T细胞。然而，在这方面， 在CNS实质内没有常规的淋巴管。或者，有人假设 抗原、抗原提呈细胞和CSF可从CNS流入筛状结构附近的淋巴管， 板或硬脑膜，以维持流体稳态和抗原引流在稳态条件下，但知之甚少 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淋巴管生成 在实验性自身免疫性脑脊髓炎（EAE），多发性硬化症的小鼠模型。我们的初步 数据显示，筛状板附近的这些新淋巴管在功能上能够排出CSF， 曾经在中枢神经系统实质中的细胞。我们进一步发现，在EAE期间，VEGFC蛋白由 浸润巨噬细胞和树突状细胞，以促进VEGFR 3依赖性新淋巴管生成， 筛板这些数据首次描述了在移植过程中筛板附近的新淋巴管生成。 神经炎症该项目的长期目标是确定 筛状板附近新生淋巴管对自身免疫和中枢神经系统卒中的影响。 本建议的具体目标是（1）确定驱动的特征和监管机制 筛板附近的新生淋巴管生成（目的1）;（2）检测新生淋巴管的功能 筛状板附近，并将其与不同的CNS区域解剖学进行比较（目的2）;以及（3）了解 加重或抑制筛板附近新淋巴管生成的转化价值， CNS疾病（目标3）。 药理学抑制或加重新淋巴管生成以调节CNS疾病的病理 可能对中枢神经系统自身免疫和缺血性创伤具有潜在的治疗价值。