The role of oligodendrocyte progenitor cells in neuroinflammation

少突胶质祖细胞在神经炎症中的作用

• 批准号: 10355928
• 负责人: Alban P Gaultier
• 金额: $ 46.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355928
• 关键词: Address; Adult; Animal Model; Antigen Presentation; Antigens; Astrocytes; Axon; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Chromium; Cicatrix; Clonality; Cross Presentation; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Dendritic Cells; Development; Disease; Disease Progression; Excision; Experimental Autoimmune Encephalomyelitis; Foundations; Generations; Genetic; Goals; Home; Homeostasis; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; LDL-Receptor Related Protein 1; Lead; Light; Lipoprotein Receptor; Mediating; Microglia; Modeling; Morphology; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Pathologic; Pathway interactions; Peripheral; Phagocytes; Phagocytosis; Pharmacology; Play; Population; Process; Production; Proteins; Publishing; Quality of life; Recruitment Activity; Reporting; Research; Research Proposals; Role; Site; Specificity; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Vision; Work; cell type; chronic demyelination; cytokine; disability; genetic manipulation; immune function; improved; in vivo; innovation; insight; monocyte; mouse model; multiple sclerosis patient; myelination; neuroinflammation; neuron loss; new therapeutic target; novel; oligodendrocyte progenitor; prevent; progenitor; receptor; recruit; remyelination; repaired; response; scavenger receptor; single cell sequencing; stem cell function; stem cells; therapy development; transcriptome sequencing; white matter

ABSTRACT: The central nervous system (CNS) is home to three major classes of glia: astrocytes, microglia, and oligodendrocytes. Recently, a fourth class of glia has been recognized, called oligodendrocyte progenitor cells (OPCs). Like microglia, OPCs have a stellate morphology and are “tiled”, spanning defined territories across the gray and the white matter. For a long time, our vision of OPC function was limited to generation of mature oligodendrocytes. This dogma is challenged by recently published studies suggesting that OPCs could serve other role(s) in the CNS. Indeed, a nascent body of work is uncovering an intricate role for these cells in the context of inflammation. For example, OPCs have been shown to express cytokines and participate in the recruitment of peripheral monocytes. Following injury, OPCs can release IL-33, a key alarmin that orchestrates the immune response. Finally, in animal models of MS, OPCs have been shown to present antigen and respond to inflammatory cytokines, suggesting that they are active regulators of disease in MS. Taken together, these data demonstrate that OPCs are not simple bystanders, but could participate in the inflammatory response in the CNS. Our long-term goal is to shed light on the role of OPCs in the CNS, focusing on their alternate immune functions, in an effort to develop novel MS therapeutics. The foundation of this proposal is formed by the observations that low-density lipoprotein receptor-related protein-1 (LRP1) is expressed by OPCs and functions to facilitate phagocytosis of myelin and antigen cross- presentation. Our preliminary data show that deletion of LRP1 in OPCs promotes remyelination in animal models of MS. Our central hypothesis is that, during demyelination, OPCs cross-present antigens to CD8 T cells in an LRP1 dependent manner, leading to OPC cell death and impairing remyelination. Guided by strong evidence, this hypothesis will be addressed by pursuing three specific aims: 1: Assess the role of LRP1 in the OPC-mediated inflammatory response, 2: Assess pharmacological and genetic manipulation of OPC antigen cross-presentation in promoting myelin repair, 3: Determine the impact of OPC antigen cross-presentation on T cell functions. We will use in vivo animal models of demyelination (cuprizone and EAE) and in vitro cultures of OPCs and T cells to test our hypothesis. Our approach is innovative because it will utilize novel mouse strains and state of the start single-cell sequencing to generate new scientific knowledge of alternate functions of OPCs in the context of remyelination. The proposed research is significant because it will test whether antigen presentation via LRP1 represents a novel target for therapy development in MS and other demyelinating disorders. The insights gained from our studies will lead to fundamental advances in understanding how OPCs contribute to inflammation.

抽象的： 中枢神经系统（CNS）是三个主要类别胶质的家园：星形胶质细胞，小胶质细胞和 少突胶质细胞。最近，已经识别出第四类的神经胶质，称为少突胶质细胞祖细胞 （OPC）。像小胶质细胞一样，OPC具有出色的形态，并且是“瓷砖”，跨越了整个领土 灰色和白色物质。长期以来，我们对OPC功能的愿景仅限于成熟的产生 少突胶质细胞。最近发表的研究挑战了这种教条，表明OPC可以服务 中枢神经系统中的其他角色。实际上，新生的工作正在发现这些细胞在这些细胞中的复杂作用 炎症的背景。例如，已经证明OPC表达细胞因子并参与 募集周围单核细胞。受伤后，OPC可以释放IL-33，这是一个钥匙警报，可以编排 免疫反应。最后，在MS的动物模型中，已经证明OPC可以呈现抗原并做出反应 炎性细胞因子，表明它们是MS中疾病的积极调节剂。总的来说，这些 数据表明，OPC不是简单的旁观者，但可以参与 中枢神经系统。我们的长期目标是阐明OPC在中枢神经系统中的作用，重点关注其替代免疫力 功能，以开发新的MS治疗。 该提案的基础是由低密度脂蛋白受体相关的观察结果形成的 蛋白-1（LRP1）用OPC表达和功能，以促进髓磷脂和抗原交叉的吞噬作用 推介会。我们的初步数据表明，OPC中LRP1的缺失促进了动物模型中的再生。 MS。我们的中心假设是，在脱髓鞘期间，OPC与CD8 T细胞交叉抗原 以LRP1的方式依赖，导致OPC细胞死亡并损害了remer髓。在强者的指导下 证据，将通过追求三个具体目标来解决这一假设：1：评估LRP1在 OPC介导的炎症反应，2：评估OPC抗原的药理和遗传操纵 促进髓磷脂修复方面的交叉呈递，3：确定OPC抗原交叉呈递对T的影响 细胞功能。我们将使用脱髓鞘的体内动物模型（Cuprizone和Eae）和体外培养物 OPC和T细胞检验我们的假设。我们的方法是创新的，因为它将利用新颖的鼠标菌株 和开始单细胞测序的状态，以生成OPC替代功能的新科学知识 在再髓的背景下。 拟议的研究很重要，因为它将测试通过LRP1的抗原呈递是否代表 MS和其他脱髓鞘疾病中治疗发展的新目标。从我们那里获得的见解 研究将导致理解OPC如何促进炎症的基本进展。