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.

项目总结/文摘