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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

基本信息

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
项目类别：
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

项目摘要

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，其特征是通过脱髓鞘和轴突损失。脱髓鞘病变是由细胞浸润定义的主要由 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 - 衍生巨噬细胞（BMDM）和常驻小胶质细胞。了解它们的相互作用对于 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因子和带髓鞘轴突，最终导致组织损伤。然而，T 细胞如何指导骨髓细胞，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。该模型提供了一个独特的工具来剖析 Th1 与 Th17 细胞如何在脱髓鞘过程中调节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：改变小胶质细胞致病功能并促进 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。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功能和髓磷脂损伤 BMDM 的作用，以及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小胶质细胞处于独特的炎症环境中。通过揭示小胶质细胞如何响应突出的 T 细胞细胞因子，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，可能会带来新的治疗靶点。