T cell-dependent regulation of microglia demyelinating functions

摘要 多发性硬化（MS）是一种中枢神经系统（CNS）慢性炎症性疾病， 脱髓鞘和轴突缺失脱髓鞘病变定义为细胞浸润， 主要是T淋巴细胞和两种不同类型的骨髓细胞，即CNS浸润骨髓- 衍生的巨噬细胞（BMDM）和驻留的小胶质细胞。了解它们的相互作用对MS至关重要 发病机制，因为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 因子和剥离有髓鞘的轴突，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。 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 功能，以及剥离和吞噬细胞髓鞘，仍然知之甚少。本提案的总体目标是 确定调节小胶质细胞和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细胞功能如何特异性地促进 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剖析Th1细胞与Th17细胞 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作用： 改变小胶质细胞致病功能和促进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的反应性调节其脱髓鞘功能，而不依赖于BMDM。 更具体地说，这一目标将确定小胶质细胞氧化爆发对髓鞘损伤的贡献，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细胞如何改变小胶质细胞效应功能和髓鞘损伤，在存在或不存在的情况下， 以及这种作用是否直接依赖于IL-17和/或GM-CSF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 小胶质细胞在一个独特的炎症环境中。通过揭示小胶质细胞如何对突出的T细胞应答， 细胞因子，这一建议将提供新的见解的直接贡献，小胶质细胞病变的形成， MS患者，可能导致新的治疗靶点。

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.