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.

摘要 多发性硬化症(MS)是一种慢性炎症性中枢神经系统(CNS)疾病 通过脱髓鞘和轴突丢失。脱髓鞘病变的定义是细胞浸润物 主要是T淋巴细胞和两种不同类型的髓系细胞，即中枢神经系统浸润性骨髓- 来源的巨噬细胞(BMDM)和常驻的小胶质细胞。了解它们的相互作用对多发性硬化至关重要。 发病机制，由于T细胞产生的细胞因子和趋化因子促进髓系细胞群产生毒物 因子和剥离有髓轴突，最终导致组织损伤。然而，T细胞如何指示髓系细胞， 以及BMDM和小胶质细胞对组织损伤和残疾的相对贡献尚不清楚。 特别是在MS患者中发现的Th1和Th17细胞如何影响BMDM和/或小胶质细胞表达毒性 对于髓鞘的功能，以及条带和吞噬髓鞘，人们仍然知之甚少。这项提案的总体目标是 明确体内调节小胶质细胞和BMDM积极参与脱髓鞘的机制 进程。 使用一种独特的小鼠病毒性脑脊髓炎模型，在该模型中，小胶质细胞在缺失的情况下介导脱髓鞘 对于BMDM和Th17反应，这一提议将定义不同的T细胞功能如何具体促进 小胶质细胞介导的脱髓鞘。这个模型提供了一个独特的工具来分析Th1和Th17细胞如何 调节脱髓鞘过程中的小胶质细胞效应器功能。根据我们的初步数据，我们假设 严格的Th1条件促使小胶质细胞介导脱髓鞘，而Th17反应可以通过以下方式改变这一效应 改变小胶质细胞的致病功能，促进BMDM介导的脱髓鞘。目标1将测试如何 小胶质细胞对T细胞来源的干扰素-γ的反应性调节其脱髓鞘功能，而不依赖于骨髓基质。 更具体地说，这个目标将定义小胶质细胞氧化爆发对髓鞘损伤的贡献，以及 确定小胶质细胞吞噬功能的TREM-2调节是否有助于脱髓鞘。目标 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器的功能和髓鞘损伤 这种作用是否直接依赖于IL-17和/或GM-CSF的分泌。基因阵列 分析还将表征与致病功能和保护功能相关的表型标记 在不同的炎症环境中的小胶质细胞。通过揭示小胶质细胞如何对突出的T细胞做出反应 细胞因子，这一提议将为小胶质细胞在脑内病变形成中的直接作用提供新的见解 多发性硬化症患者，可能导致新的治疗靶点。