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: 10547816
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547816
• 关键词: Address; Affect; Automobile Driving; Axon; Bone Marrow; CCL2 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Central Nervous System; 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; IL17 gene; Immune; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interferon Gamma Receptor Complex; Interferon Type II; Lesion; Macrophage; Maus Elberfeld virus; Mediating; Mediator; Microglia; Modeling; Morphology; Multiple Sclerosis; Mus; Myelin; Myelogenous; Myeloid Cells; Nitrogen; Outcome; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytes; Play; Population; Process; Receptor Signaling; Regulation; Repression; Respiratory Burst; Role; Signal Transduction; T cell regulation; T cell response; T-Lymphocyte; TREM2 gene; Technology; Testing; Th1 Cells; Tissues; Virus; chemokine; chronic inflammatory disease; cytokine; defined contribution; disability; glial activation; immune cell infiltrate; in vivo; inflammatory milieu; insight; 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) 是一种中枢神经系统 (CNS) 的慢性炎症性疾病，其特征是 脱髓鞘和轴突损失定义为细胞浸润。 主要由 T 淋巴细胞和两种不同类型的骨髓细胞组成，即中枢神经系统浸润骨髓 - 了解衍生巨噬细胞 (BMDM) 和驻留小胶质细胞的相互作用对于 MS 至关重要。 发病机制，T 细胞产生的细胞因子和趋化因子促进骨髓细胞群产生毒性 然而，T 细胞如何指导髓系细胞， 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。 具体而言，多发性硬化症患者中的 Th1 和 Th17 细胞如何影响 BMDM 和/或小胶质细胞表达毒性 功能以及条带和吞噬细胞髓磷脂仍然知之甚少 该提案的总体目标是。 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，其中小胶质细胞在不存在的情况下介导脱髓鞘 BMDM 和 Th17 反应，该提案将定义不同的 T 细胞功能如何具体促进 小胶质细胞介导的脱髓鞘作用提供了一种独特的工具来剖析 Th1 细胞与 Th17 细胞的关系。 根据我们的初步数据，我们认为在脱髓鞘过程中调节小胶质细胞效应功能。 严格的 Th1 条件驱动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种效应： 目标 1 将测试如何改变小胶质细胞致病功能并促进 BMDM 介导的脱髓鞘。 小胶质细胞对 T 细胞衍生的 IFN-γ 的反应可独立于 BMDM 调节其脱髓鞘功能。 更具体地说，该目标将确定小胶质细胞氧化爆发对髓磷脂损伤的贡献，以及 确定 TREM-2 对小胶质细胞吞噬功能的调节是否有助于脱髓鞘。 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功能和髓磷脂损伤 BMDM 的影响，以及这种效应是否直接依赖于 IL-17 和/或 GM-CSF 的分泌。 分析还将表征与致病功能和保护功能相关的表型标记 通过揭示小胶质细胞如何响应显着的 T 细胞，研究小胶质细胞在不同炎症环境中的作用。 细胞因子，该提案将为小胶质细胞对病变形成的直接贡献提供新的见解 多发性硬化症患者，可能会产生新的治疗靶点。

项目成果

Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.

Trem2 缺陷会损害恢复和吞噬作用，并在病毒诱导的脱髓鞘过程中调节骨髓基因表达。

• 发表时间: 2022-11-04
• 作者: Hwang, Mihyun;Savarin, Carine;Kim, Jihye;Powers, Jennifer;Towne, Natasha;Oh, Hyunsuk;Bergmann, Cornelia C
• 通讯作者: Bergmann, Cornelia C