Regulation of Neuroinflammation by Meningeal Lymphatics

脑膜淋巴管对神经炎症的调节

基本信息

批准号：
10581900
负责人：
Zsuzsanna Fabry
金额：
$ 41.27万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581900
关键词：
Adhesions Alzheimer&apos s Disease Antigen Presentation Antigen-Presenting Cells Antigens Area Binding Brain Brain Diseases Brain Drains CNS autoimmunity Cell Communication Cells Central Nervous System Diseases Cues Data Dendritic Cell Pathway Dendritic Cells Disease Disease Progression Drainage procedure Endothelial Cells Failure Flow Cytometry Fluid Balance Foundations Gene Expression Genomics Glioblastoma Growth Homeostasis ITGAX gene Immune Immune response Immune system Immunity Immunologics In Situ Inflammation Inflammatory Intervention Intravenous Label Leukocytes Liquid substance Location Longitudinal Studies Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphatic function Lymphoid Maps Measurable Measures Meningeal Meningeal lymphatic system Multiple Sclerosis Mus Nature Neuraxis Neuroimmune Parkinson Disease Pathway interactions Peripheral Pharmacology Population Positioning Attribute Publishing Regulation Resolution Role Route Stains Stroke Structure of choroid plexus Subarachnoid Space Synapses T-Cell Activation T-Lymphocyte Testing Therapeutic TimeLine Tissues Traumatic Brain Injury Vascular Endothelial Growth Factor C brain parenchyma cell motility cell type confocal imaging cribriform plate disorder control draining lymph node immunoregulation in vivo lymph nodes lymphatic vessel migration neuroinflammation neuropathology prevent programmed cell death ligand 1 receptor recruit single-cell RNA sequencing trafficking wasting

项目摘要

PROJECT SUMMARY/ABSTRACT The brain must maintain immunological homeostasis to prevent dysregulation and disease. Coordination of immunity in most tissues involves the drainage of antigens or antigen-presenting cells within conventional lymphatic vessels to the draining lymph nodes. In the lymph node, antigen presented to T cells, typically by dendritic cells (DCs), can initiate an immune response. Control of immune response is unique in the central nervous system as the brain parenchyma lacks conventional infiltrating lymphatic vessels and instead utilizes a combination of intra-tissue glial-dependent clearance pathways and meningeal lymphatics surrounding the brain to drain waste, antigens, fluid, and cells. Recently there has been mounting evidence implicating meningeal lymphatic vessels as passive conductors of drainage in the progression, and resolution of various neuropathologies. We previously discovered that neuroinflammation induces lymphangiogenesis of the meningeal lymphatic vessels at the cribriform plate (cp) (Hsu et al. Nat Comm. 2019). We found that in situ meningeal lymphangiogenesis was driven by VEGF-C producing DCs, and this is unique to the cp, highlighting potentially different roles for dural lymphatics in neuroinflammation depending on their precise location. Here we show single-cell RNA sequencing data revealing that neuroinflammation induces cribriform plate lymphatic endothelial cell (cpLECs) gene expression related to antigen presentation, leukocyte adhesion, and immunoregulation. This indicates that cpLECs are not just passive conductors of drainage, but active contributors to the formation of a neuroimmune regulatory niche. We hypothesize that during neuroinflammation, the cribriform lymphatics represent an immunoregulatory niche in which migratory DCs drained from the brain are retained and communicate with cpLECs to regulate downstream immune response and homeostasis of the central nervous system. The pathways of DCs traffic through the brain to the cribriform lymphatics, the mechanism of their interaction with cpLECs, and the functional consequence of these interactions on both cell types and on the formation of a neuroimmune niche are not known. The long-term objective of this project is to define the pathways and dynamics of interactions between dendritic cells and the cribriform plate lymphatics to understand the regulation of brain homeostasis and disease. The specific objectives of this proposal are to map the timeline, origin, and mechanism of dendritic cell - cribriform lymphatic endothelial cells interaction (DC-cpLEC) in the meningeal lymphatic vessels at the cribriform plate (Aim 1); to define expressional consequences of the interaction between DCs and cpLECs (Aim 2), and to examine the impact of DC-cpLEC interactions on lymphatic functionality and immunity (Aim 3). Pharmacological manipulation of the cross-talk between dendritic cells and cribriform lymphatic endothelial cells in CNS diseases may have potential therapeutic value for diseases related to CNS autoimmunity and homeostasis.

项目概要/摘要大脑必须维持免疫稳态，以防止失调和疾病。协调大多数组织中的免疫涉及传统抗原或抗原呈递细胞的排出淋巴管至引流淋巴结。在淋巴结中，抗原呈递给 T 细胞，通常通过树突状细胞（DC）可以启动免疫反应。免疫反应的控制在中枢是独一无二的神经系统，因为脑实质缺乏传统的浸润淋巴管，而是利用组织内神经胶质依赖性清除途径和大脑周围的脑膜淋巴管的组合排出废物、抗原、液体和细胞。最近，越来越多的证据表明脑膜炎淋巴管作为引流的被动导体，在各种疾病的进展和解决中神经病理学。我们之前发现神经炎症会诱导淋巴管生成筛板处的脑膜淋巴管 (cp) (Hsu et al. Nat Comm. 2019)。我们在现场发现脑膜淋巴管生成是由产生 VEGF-C 的 DC 驱动的，这是 cp 所独有的，强调硬脑膜淋巴管在神经炎症中可能发挥不同的作用，具体取决于它们的精确位置。在这里我们显示单细胞 RNA 测序数据揭示神经炎症诱导筛板淋巴管内皮细胞 (cpLEC) 与抗原呈递、白细胞粘附和相关的基因表达免疫调节。这表明 cpLEC 不仅是排水的被动导体，而且是主动的排水导体。有助于神经免疫调节生态位的形成。我们假设在神经炎症期间，筛状淋巴管代表免疫调节生态位，其中迁移性 DC 从大脑中排出被保留并与 cpLEC 通信以调节下游免疫反应和体内平衡中枢神经系统。 DC 的通路通过大脑到达筛状淋巴管，即它们与 cpLEC 相互作用的机制，以及这些相互作用对两种细胞的功能结果神经免疫生态位的类型和形成尚不清楚。该项目的长期目标是定义树突之间相互作用的途径和动态细胞和筛板淋巴管，以了解大脑稳态和疾病的调节。这该提案的具体目标是绘制树突状细胞 - cribriform 的时间线、起源和机制筛板脑膜淋巴管中的淋巴内皮细胞相互作用（DC-cpLEC）（目标 1）；定义 DC 和 cpLEC 之间相互作用的表达结果（目标 2），并检查 DC-cpLEC 相互作用对淋巴功能和免疫的影响（目标 3）。树突状细胞和筛状淋巴内皮细胞之间相互作用的药理学操作中枢神经系统疾病可能对中枢神经系统自身免疫相关疾病具有潜在的治疗价值体内平衡。