T cell-dependent regulation of microglia demyelinating functions

小胶质细胞脱髓鞘功能的 T 细胞依赖性调节

• 批准号: 10332745
• 负责人: Cornelia Bergmann
• 金额: $ 35.22万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332745
• 关键词: Address; Affect; Automobile Driving; Axon; Bone Marrow; CCL2 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Central Nervous System Diseases; Coronavirus; Cues; Data; Demyelinations; Development; Disease; Effector Cell; Exhibits; Experimental Autoimmune Encephalomyelitis; Gene Expression; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interferon Gamma Receptor Complex; Interferon Type II; Interleukin-17; Lesion; Leucocytic infiltrate; Maus Elberfeld virus; Mediating; Mediator of activation protein; Microglia; Modeling; Morphology; Multiple Sclerosis; Mus; Myelin; Myelogenous; Myeloid Cells; Neuraxis; Nitrogen; Outcome; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytes; Play; Population; Process; Receptor Signaling; Regulation; Respiratory Burst; Role; Signal Transduction; T cell regulation; T cell response; T-Lymphocyte; TREM2 gene; Technology; Testing; Th1 Cells; Tissues; Tumor-infiltrating immune cells; Virus; base; chemokine; chronic inflammatory disease; cytokine; defined contribution; disability; in vivo; inflammatory milieu; insight; macrophage; monocyte; mouse model; multiple sclerosis patient; nano-string; new therapeutic target; oxidative damage; phenotypic biomarker; receptor; recruit; response; tool; uptake

Abstract Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are defined by cellular infiltrates composed predominantly of T lymphocytes and two distinct types of myeloid cells, namely CNS infiltrating bone marrow- derived macrophages (BMDM) and resident microglia. Understanding their interplay is essential to MS pathogenesis, as T cell-produced cytokines and chemokines promote myeloid cell populations to produce toxic factors and strip myelinated axons, culminating in tissue damage. However, how T cells instruct myeloid cells, as well as the relative contributions of BMDM and microglia to tissue damage and disability, are unclear. Specifically how Th1 and Th17 cells, both found in MS patients, affect BMDM and/or microglia to express toxic functions, as well as strip and phagocyte myelin, are still poorly understood. The overall goal of this proposal is to define in vivo mechanisms that regulate microglia and BMDM to actively participate in the demyelinating process. Using a unique murine virus encephalomyelitis model in which microglia mediate demyelination in the absence of BMDM and Th17 response, this proposal will define how distinct T cell functions specifically promote microglia-mediated demyelination. This model provides a unique tool to dissect how Th1 versus Th17 cells regulate microglia effector functions during demyelination. Based on our preliminary data, we hypothesize that strict Th1 conditions drive microglia to mediate demyelination, while Th17 response can modify this effect by altering microglial pathogenic functions and promoting BMDM-mediated demyelination. Aim 1 will test how microglial responsiveness to T cell-derived IFN-γ regulates their demyelinating function independent of BMDM. More specifically, this aim will define the contribution of microglia oxidative burst to myelin damage, as well as determine whether TREM-2 modulation of microglial phagocytic functions can contribute to demyelination. Aim 2 will reveal how Th17 cells alters microglia effector functions and myelin damage, in the presence or absence of BMDM, and whether this effect is directly dependent upon IL-17 and/or GM-CSF secretion. Gene array analysis will also characterize phenotypic markers associated with the pathogenic versus protective functions of microglia in a distinct inflammatory environment. By revealing how microglia respond to prominent T cell cytokines, this proposal will provide new insights into the direct contribution of microglia to lesion formation in MS patients, potentially leading to new therapeutic targets.

抽象的 多发性硬化症（MS）是中枢神经系统（CNS）的慢性炎症性疾病 通过脱髓鞘和轴突损失。脱髓鞘病变由组成的细胞浸润定义 主要是T淋巴细胞和两种不同类型的髓样细胞，即CNS浸润骨髓 衍生的巨噬细胞（BMDM）和居民小胶质细胞。了解他们的相互作用对MS至关重要 发病机理，因为T细胞产生的细胞因子和趋化因子促进髓样细胞群体产生有毒 因素和剥离髓样细胞，最终导致组织损伤。但是，T细胞如何指导髓样细胞， 尚不清楚BMDM和小胶质细胞对组织损伤和残疾的相对贡献。 特别是在MS患者中发现的Th1和Th17细胞如何影响BMDM和/或小胶质细胞以表达有毒 功能以及条带和吞噬细胞髓磷脂，仍然知之甚少。该提议的总体目标是 定义调节小胶质细胞和BMDM积极参与脱髓鞘的体内机制 过程。 使用独特的鼠病毒脑脊髓炎模型，其中小胶质细胞介质在不存在的情况下脱髓鞘 BMDM和TH17响应的响应，该提案将定义不同的T细胞功能如何特别促进 小胶质细胞介导的脱髓鞘。该模型提供了一种独特的工具，可以剖析Th1与Th17单元的方式 调节小胶质细胞效应子在脱髓鞘过程中的功能。根据我们的初步数据，我们假设 严格的Th1疾病驱动小胶质细胞介导脱髓鞘，而Th17响应可以通过 改变小胶质的致病功能并促进BMDM介导的脱髓鞘。 AIM 1将测试如何 小胶质细胞对T细胞衍生的IFN-γ的反应性调节其脱髓鞘功能与BMDM无关。 更具体地说，此目标将定义小胶质细胞氧化爆发对髓磷脂损伤的贡献，以及 确定小胶质细胞功能的Trem-2调节是否有助于脱髓鞘。目的 2将揭示Th17细胞在存在或不存在的情况下如何改变小胶质细胞效应子功能和髓磷脂损伤 BMDM的效果是否直接取决于IL-17和/或GM-CSF分泌。基因阵列 分析还将表征与致病功能相关的表型标记 在独特的炎症环境中的小胶质细胞。通过揭示小胶质细胞对突出的T细胞的反应 细胞因子，该建议将为小胶质细胞对病变形成的直接贡献提供新的见解。 MS患者，可能导致新的治疗靶标。