Regulation of Neuroinflammation by Meningeal Lymphatics

项目摘要/摘要 大脑必须保持免疫平衡，以防止调节失调和疾病。协调 在大多数组织中，免疫涉及常规免疫中抗原或抗原提呈细胞的排出。 淋巴管通向引流的淋巴结。在淋巴结中，抗原呈递给T细胞，通常是通过 树突状细胞(DC)可以启动免疫反应。免疫反应的控制在中央是独一无二的 神经系统作为脑实质，缺乏常规的浸润性淋巴管，而是利用 脑组织内神经胶质依赖性清除通路和脑膜淋巴管的联合作用 排出废物、抗原、液体和细胞。最近有越来越多的证据表明脑膜有牵连 淋巴管作为引流的被动导体在各种疾病的进展和消退中 神经病理学。我们先前发现，神经炎症诱导淋巴管生成 筛板上的脑膜淋巴管(Cp)(Hsu等人)。NAT Comm。2019年)。我们在现场发现 脑膜淋巴管生成是由产生血管内皮生长因子-C的树突状细胞驱动的，这是cp所特有的，强调 硬脑膜淋巴管在神经炎症中可能扮演不同的角色，这取决于它们的确切位置。在这里我们 显示单细胞RNA测序数据显示神经炎症诱导筛板淋巴 内皮细胞(CpLECs)基因表达与抗原提呈、白细胞黏附和 免疫调节。这表明cpLECs不仅是被动的引流导体，而且是主动的引流导体。 神经免疫调节生态位形成的贡献者。我们假设在神经炎症期间， 筛状淋巴管代表了一个免疫调节小室，在那里迁徙的树突状细胞从大脑中流出。 被保留并与cpLECs沟通，以调节下游的免疫反应和体内平衡 中枢神经系统。树突状细胞通过大脑进入筛状淋巴管的通路 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影响 类型和关于神经免疫利基的形成尚不清楚。 该项目的长期目标是确定树突之间相互作用的路径和动力学 细胞和筛板淋巴管，以了解大脑稳态和疾病的调节。这个 本提案的具体目标是绘制树突状细胞-筛状细胞的时间线、来源和机制 筛板脑膜淋巴管内淋巴管内淋巴内皮细胞相互作用 (目标1)；界定DC和cpLEC之间相互作用的表现后果(目标2)，并 研究DC-cpLEC相互作用对淋巴功能和免疫的影响(目标3)。 树突状细胞与筛状淋巴管内皮细胞间相互作用的药理学调控 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 动态平衡。

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.