Regulation of Neuroinflammation by Meningeal Lymphatics

脑膜淋巴管对神经炎症的调节

• 批准号: 10682552
• 负责人: Zsuzsanna Fabry
• 金额: $ 41.65万
• 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/10682552
• 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; Central Nervous System Diseases; Communication; 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; Infiltration; Inflammation; Inflammatory; Intervention; Intravenous; Label; Leukocytes; Liquid substance; Location; Longitudinal Studies; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphoid; Maps; Measurable; Measures; Meningeal; Meningeal lymphatic system; Multiple Sclerosis; Mus; Nature; Neuroimmune; Parkinson Disease; Pathway interactions; Peripheral; Population; Positioning Attribute; Publishing; Regulation; Resolution; Role; Route; Stains; Stroke; Structure of choroid plexus; Subarachnoid Space; Synapses; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Traumatic Brain Injury; VEGFC gene; Vascular Endothelial Growth Factor C; Visualization; 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; pharmacologic; prevent; programmed cell death ligand 1; receptor; recruit; single-cell RNA sequencing; timeline; 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.

项目摘要/摘要 大脑必须保持免疫稳态以预防失调和疾病。协调 大多数组织中的免疫力涉及传统中抗原或抗原细胞的排水 淋巴血管到排水淋巴结。在淋巴结中，抗原向T细胞呈现，通常是由 树突状细胞（DC）可以引发免疫反应。免疫反应的控制在中央是独一无二的 神经系统由于脑实质缺乏常规的浸润淋巴管，而是利用 组织内神经胶质依赖性间隙途径和脑膜淋巴管的结合 排出废物，抗原，液体和细胞。最近有持续的证据暗示脑膜 淋巴管作为排水的被动导体，并分辨出各种 神经病理学。我们以前发现，神经炎症诱导了 环形板（CP）处的脑膜淋巴管（Hsu等人NatComm。2019）。我们发现原位 脑膜淋巴管生成是由VEGF-C产生DC驱动的，这是CP独有的，突出显示 硬脑膜淋巴机在神经炎症中的潜在不同，具体取决于其精确位置。我们在这里 显示单细胞RNA测序数据，表明神经炎症会诱导环形板淋巴管 内皮细胞（CPLECS）基因表达与抗原表现，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 形成神经免疫调节生态位的贡献者。我们假设在神经炎症期间， 环形淋巴管代表了一种免疫调节的生态位，其中从大脑中排出的迁移DC 保留并与CPLEC进行沟通，以调节下游免疫反应和稳态 中枢神经系统。 DCS通过大脑的途径传递到丝布状淋巴管， 它们与CPLEC相互作用的机制，以及这些相互作用在两个细胞上的功能结果 尚不清楚类型和形成神经免疫性小众。 该项目的长期目标是定义树突状相互作用的途径和动态 细胞和环形板淋巴管，以了解大脑稳态和疾病的调节。这 该提案的特定目标是绘制树突状细胞的时间表，起源和机制 - 筛状的 淋巴内皮细胞的相互作用（DC-CPLEC）在脑膜淋巴管的膜状板板的 （目标1）;定义DC与CPLEC之间相互作用的表达后果（AIM 2），以及 检查DC-CPLEC相互作用对淋巴功能和免疫力的影响（AIM 3）。 树突状细胞和丝布状淋巴内皮细胞之间串扰的药理操纵 在中枢神经系统中，与中枢神经系统自身免疫性有关的疾病可能具有潜在的治疗价值 稳态。