Restoration of homeostatic microglia in CNS inflammation

项目总结 多发性硬化症(MS)是一种慢性炎症性中枢神经系统(CNS)疾病 局灶性T细胞和髓样细胞浸润，导致脱髓鞘和神经功能丧失。已激活 在活动性或慢性MS斑块中，小胶质细胞和巨噬细胞是主要的炎症细胞，它们 坚持继发性进展性多发性硬化症尽管我们对多发性硬化症病理生理学的理解有所进步，但仍有 对先天介导的继发性多发性硬化症进行最小限度的疾病修正治疗或预防。 我们最近发现在小胶质细胞中由转化生长因子β和载脂蛋白E信号驱动的相互拮抗的通路， 决定了动态型(M0)和神经退行性变(MGnD)表型之间的表型转换。使用 通过系统生物学的方法，我们确定了M0-和MGnD-的主要转录和表观遗传调节因子。 小胶质细胞。最后，我们揭示了转化生长因子β-干扰素γ信号在外周血单核细胞重编程中的新作用。 转化为具有M0分子特征的小胶质细胞样细胞。根据我们公布的和初步的数据，我们 假设调节载脂蛋白-转化生长因子β/干扰素γ通路将恢复动态平衡耐受的小胶质细胞 改善EAE。我们将从以下几个方面阐述我们的假设： 目的1：通过载脂蛋白-转化生长因子β/干扰素γ信号通路补充EAE中M0平衡的小胶质细胞 为此，我们将确定：1)转化生长因子β/干扰素γ信号转导对M0-小胶质细胞补给的影响 2)载脂蛋白-转化生长因子β信号调控的小胶质细胞表型调控网络 3)EAE高峰期和恢复期小胶质细胞表型转换的命运图分析。 目的2：通过载脂蛋白E-转化生长因子β/干扰素γ途径将单核细胞重编程为类MG细胞 病人 为此，我们将确定1)在Ly6CHi单核细胞中靶向APOE是否有助于获得 2)转化生长因子β/干扰素介导的分子机制 LY6CHI单核细胞重编程；3)APOE-转化生长因子β/干扰素通路的调控 从MS患者分离的CD14/CD16单核细胞诱导M0-小胶质细胞转录程序 作为一种治疗进行性多发性硬化症的新方法 成功的完成将导致：1)鉴定载脂蛋白-转化生长因子β/干扰素γ介导的分子机制 小胶质细胞和单核细胞表型调控中的信号转导 2)了解载脂蛋白-转化生长因子β/干扰素γ信号在外周血重编程中的作用 在EAE和MS患者中，单核细胞转化为动态平衡的小胶质细胞样细胞。

PROJECT SUMMARY Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by focal T cell and myeloid cell infiltrates leading to demyelination and loss of neurologic function. Activated microglia and macrophages are the predominant inflammatory cells in active or chronic MS plaques, and they persist in secondary-progressive MS. Despite advances in our understanding of MS pathophysiology, there are minimal disease-modifying treatments or preventions for innate-mediated, secondary-progressive forms of MS. We recently found that mutually antagonistic pathways driven by TGFβ and APOE signaling in microglia, dictate a phenotypic switch between homeostatic (M0) and neurodegenerative (MGnD) phenotypes. Using a systems biology approach, we identified major transcriptional and epigenetic regulators of M0- and MGnD- microglia. Finally, we reveal a new role for TGFβ-IFNγ signaling in the reprogramming of peripheral monocytes into microglia-like cells with the M0-molecular signature. Based on our published and preliminary data, we hypothesize that modulating the APOE-TGFβ/IFNγ pathway will restore the homeostatic-tolerogenic microglia and ameliorate EAE. We will address our hypothesis in the following aims: Aim 1: Replenish M0-homeostatic microglia via APOE-TGFβ/IFNγ signaling in EAE In this Aim, we will determine 1) the impact of TGFβ/IFNγ signaling on the replenishment of M0-microglia in EAE; 2) the regulatory networks controlled by APOE-TGFβ signaling underlying microglia phenotype regulation in EAE; and 3) fate-map analysis of microglia phenotype switch during peak and recovery stage of EAE. Aim 2: Reprogram monocytes into MG-like cells via APOE-TGFβ/IFNγ pathway in EAE and from MS patients In this Aim, we will determine 1) whether targeting Apoe in Ly6CHi monocytes facilitates the acquisition of the M0-microglial transcriptional program; 2) the molecular mechanisms underlying TGFβ/IFN-mediated reprogramming of Ly6CHi monocytes; and 3) whether modulation of the APOE-TGFβ/IFN pathway in CD14+/CD16– monocytes isolated from MS subjects induces the M0-microglial transcriptional program to serve as a novel therapeutic approach for progressive MS. Successful completion will result in: 1) identification of molecular mechanisms mediated by APOE-TGFβ/IFNγ signaling in microglia and monocyte phenotype regulation that contribute to the development, progression and resolution of EAE, and 2) understanding the role of APOE-TGFβ/IFNγ signaling in reprogramming of peripheral monocytes into homeostatic microglia-like cells in EAE and from MS patients.