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: 10445061
• 负责人: Anthony J Filiano
• 金额: $ 39.47万
• 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/10445061
• 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 - 巨噬细胞相互作用保持CNS免疫耐受性 抽象的 多发性硬化症（MS）是中枢神经系统（CNS）的自身免疫性疾病，其中浸润T细胞 最终导致髓鞘破坏。 T细胞最初积聚在大脑的血管周空间中， 在激活和浸润到该的之前，它们必须与抗原呈递细胞相互作用的脑膜 实质。这表明血管周空间中的免疫相互作用可以用作检查点，并且 确定浸润T细胞的命运。巨噬细胞和周细胞是血管内的两个重要细胞 大脑和脑膜的空间。在稳态条件下，边界巨噬细胞具有免疫 监测表型和表达表面标志物的典型巨噬细胞，这些巨噬细胞有助于治愈组织。这 在该状态下维持中枢神经系统边界巨噬细胞的信号尚不清楚。周细胞也居住在 血管周空间，是神经血管单元的关键组成部分，它们调节血液流动， 血管生成，血脑屏障（BBB）和神经炎症。尽管每种单元格被暗示 在多发性硬化症（MS）中，尚未描述两种细胞类型之间的通信。我们的初步 数据表明，培养的周细胞通过吸引巨噬细胞抑制T细胞的激活。 周细胞直接接触巨噬细胞并将其重新编程以下调基因的抗原需求 表现和T细胞激活。周细胞/巨噬细胞相互作用是由脂蛋白受体介导的 巨噬细胞上的相关蛋白质（LRP），并依赖于周细胞中的p-体。 P-Bodies无膜， 含有富含调节功能的mRNA的细胞质细胞器。在体内，周细胞居住 靠近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细胞浸润周围空间 以依赖巨噬细胞的方式进行脑膜。 T细胞进一步浸入实质 当由实质触发第二个信号时。 我们假设在稳态状态下，周细胞与周围和脑膜沟通 巨噬细胞将它们保持在免疫抑制和监测状态。这有助于免疫 大脑的特权本质。在MS中，我们假设周细胞与巨噬细胞之间的交流 分解和这种将CNS巨噬细胞释放到促炎状态，从而有助于T细胞 激活和渗入大脑。在此提案中，我们将确定周细胞是否指示周围 巨噬细胞抑制脑特异性T细胞进入实质，研究周细胞是否是否 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 为了重新编程以抑制T细胞。总体而言，该建议将调查未开发的互动 周细胞和中枢神经系统边界巨噬细胞之间。