Regulation of Neuroinflammation by Meningeal Lymphatics

脑膜淋巴管对神经炎症的调节

• 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
• 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' 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

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.

项目总结/摘要 大脑必须保持免疫稳态，以防止失调和疾病。协调 大多数组织中的免疫涉及常规免疫系统中抗原或抗原呈递细胞的排出。 淋巴管到引流淋巴结。在淋巴结中，抗原通常通过以下方式提呈给T细胞： 树突状细胞（DC）可以启动免疫应答。免疫反应的控制在中枢神经系统中是独一无二的。 作为脑实质的神经系统缺乏常规的浸润淋巴管，而是利用 组织内胶质依赖性清除途径和脑周围脑膜炎的组合 排出废物抗原体液和细胞最近有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， 神经病理学我们以前发现神经炎症诱导淋巴管生成， 筛板（cp）处的脑膜淋巴管（Hsu et al. Nat Comm. 2019）。我们发现， 脑膜淋巴管生成是由产生VEGF-C的DC驱动的，这是cp所特有的， 根据其精确位置，硬脑膜炎在神经炎症中可能具有不同的作用。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细胞 内皮细胞（cpLECs）与抗原呈递、白细胞粘附和 免疫调节这表明cpLEC不仅是排水的被动导体，而且是主动的， 有助于形成神经免疫调节生态位。我们假设在神经炎症过程中， 筛状淋巴管代表免疫调节生态位，其中迁移性DC从大脑排出 被保留并与cpLEC通信，以调节下游免疫应答和细胞内稳态。 中枢神经系统树突状细胞的通路通过大脑运输到筛状神经系统， 它们与cpLECs相互作用的机制，以及这些相互作用对两种细胞的功能后果， 类型和神经免疫生态位的形成是未知的。 这个项目的长期目标是确定树突状细胞之间相互作用的途径和动力学， 细胞和筛板细胞学，以了解脑内稳态和疾病的调节。的 该提案的具体目标是绘制筛状树突细胞的时间轴、起源和机制 淋巴管内皮细胞相互作用（DC-cpLEC）在脑膜淋巴管筛板 (Aim 1）;定义DC和cpLEC之间相互作用的表达结果（目的2），以及 检查DC-cpLEC相互作用对淋巴功能和免疫的影响（目的3）。 树突状细胞与筛状淋巴管内皮细胞间相互作用的药物调控 可能对CNS自身免疫相关疾病具有潜在的治疗价值， 体内平衡