Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance

周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受

• 批准号: 10279865
• 负责人: Anthony J Filiano
• 金额: $ 39.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279865
• 关键词: Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Biological Assay; Blood; Blood - brain barrier anatomy; Blood flow; Brain; Brain Injuries; CNS autoimmune disease; CRISPR/Cas technology; Cells; Communication; Cytoplasmic Organelle; Data; Demyelinations; Environment; Event; Experimental Autoimmune Encephalomyelitis; Family; Genes; Genetic; Genetic Polymorphism; Glycine decarboxylase; Immune; Immune Tolerance; Infiltration; Inflammation; LDL-Receptor Related Protein 1; Lead; Lesion; Lipoprotein Receptor; Mediating; Membrane; Meningeal; Meninges; Messenger RNA; Modeling; Multiple Sclerosis; Mus; Myelin; Nature; Nerve Degeneration; Neuraxis; Neurologic Symptoms; Pericytes; Peripheral; Phenotype; Process; Proteins; RNA; RNA Processing; Role; Signal Transduction; Site; Spinal Cord; Surface; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; angiogenesis; antigen-specific T cells; autoreactive T cell; cell type; genome wide association study; healing; immunosuppressed; in vivo; macrophage; mesenchymal stromal cell; migration; multiple sclerosis patient; neuroinflammation; neurovascular unit; new therapeutic target; novel; novel therapeutics; programs; scavenger receptor; trafficking; uptake

Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance ABSTRACT Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where infiltrating T cells ultimately lead to the destruction of myelin. T cells initially accumulate in the perivascular space of the brain and the meninges where they must interact with antigen presenting cells prior to activating and infiltrating into the parenchyma. This suggests immune interactions in the perivascular space may serve as a checkpoint and determine the fate of infiltrating T cells. Macrophages and pericytes are two important cells in the perivascular space of the brain and meninges. Under homeostatic conditions, border macrophages have an immuno- surveillant phenotype and express surface markers typical for macrophages that help with healing tissues. The signals that maintain CNS border macrophages in this state are unknown. Pericytes also reside in the perivascular space and are a key component of the neurovascular unit where they regulate blood flow, angiogenesis, the blood-brain barrier (BBB), and neuroinflammation. Although each cell type has be implicated in multiple sclerosis (MS), the communication between the 2 cell types has not been described. Our preliminary data demonstrate that cultured pericytes suppress the activation of T cells through engaging macrophages. Pericytes directly contact macrophages and reprogram them to downregulate genes need for antigen presentation and T cells activation. Pericytes/macrophage interactions are mediated by lipoprotein receptor- related proteins (LRP) on macrophages and dependent on p-bodies in pericytes. P-bodies are membrane-less, cytoplasmic organelles that contain mRNAs enriched in regulatory functions. In vivo, pericytes reside in close proximity to perivascular and meningeal macrophages and have the potential to interact closely with macrophages. When we deleted pericytes in vivo, CNS antigen specific T cells infiltrate the perivascular space of the meninges in a manner that was dependent on macrophages. T cells further infiltrate into the parenchyma when triggered by a second signal from the parenchymal. We hypothesize that under homeostatic conditions pericytes communicate with perivascular and meningeal macrophages to maintain them in an immunosuppressive and surveillant state. This contributes to the immuno- privileged nature of the brain. In MS, we hypothesize that communication between pericytes and macrophages breakdown and this unleashes CNS macrophages into a proinflammatory state that contributes to T cell activation and infiltration into the brain. In this proposal, we will determine if pericytes instruct perivascular macrophages to inhibit brain-specific T cells from entering the parenchyma, investigate whether pericytes reprogram CNS macrophages in vivo, and determine if macrophages must engulf components of pericytes in order to be reprogramed to suppress T cells. Overall, this proposal will investigate an unexplored interaction between pericytes and CNS border macrophages.

周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受 摘要 多发性硬化症(MS)是中枢神经系统(CNS)的一种自身免疫性疾病，其中T细胞 最终导致髓鞘的破坏。T细胞最初聚集在大脑的血管周围空间， 在激活和渗透到脑膜之前，它们必须与抗原提呈细胞相互作用的脑膜 薄壁组织。这表明血管周围间隙中的免疫相互作用可能是一个检查点 决定渗入的T细胞的命运。巨噬细胞和周细胞是血管周围的两种重要细胞。 大脑和脑膜的空间。在动态平衡条件下，边界巨噬细胞具有免疫- 监测表型和表达巨噬细胞的典型表面标志，有助于组织愈合。这个 维持中枢神经系统边界巨噬细胞处于这种状态的信号尚不清楚。周细胞也驻留在 血管周围空间是神经血管单位的关键组成部分，在那里它们调节血液流动， 血管生成、血脑屏障(BBB)和神经炎症。尽管每种细胞类型都有牵连 在多发性硬化症(MS)中，这两种细胞类型之间的联系尚未被描述。我们的预赛 数据表明，培养的周细胞通过与巨噬细胞结合来抑制T细胞的激活。 周细胞直接接触巨噬细胞并对其重新编程以下调抗原需要的基因 呈现和T细胞激活。周细胞/巨噬细胞的相互作用是由脂蛋白受体- 巨噬细胞上的相关蛋白(LRP)和周细胞中依赖的p小体。P小体是无膜的， 细胞质细胞器，含有丰富的调节功能的mRNAs。在活体内，周细胞以紧密的方式 接近血管周围和脑膜巨噬细胞，并有可能与 巨噬细胞。当我们在体内删除周细胞时，CNS抗原特异性T细胞渗透到血管周围空间 以一种依赖巨噬细胞的方式显示脑膜。T细胞进一步渗入实质。 当被来自实质的第二个信号触发时。 我们假设，在动态平衡条件下，周细胞与血管周围和脑膜沟通。 巨噬细胞使其处于免疫抑制和监测状态。这有助于免疫- 大脑的特权性质。在多发性硬化症中，我们假设周细胞和巨噬细胞之间的通讯 分解，从而释放CNS巨噬细胞进入促炎状态，从而促进T细胞 激活并渗透到大脑中。在这个方案中，我们将确定周细胞是否指导血管周围 巨噬细胞抑制脑特异性T细胞进入实质，研究周细胞 在体内重新编程CNS巨噬细胞，并确定巨噬细胞是否必须吞噬周细胞的成分 命令重新编程以抑制T细胞。总体而言，该提案将调查一个未探索的交互 在周细胞和中枢神经系统边缘巨噬细胞之间。