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.

摘要： 中枢神经系统（CNS）是三种主要类型的神经胶质细胞的家园：星形胶质细胞、小胶质细胞和神经胶质细胞。 少突胶质细胞最近，第四类神经胶质细胞被确认，称为少突胶质细胞祖细胞 （OPCs）。像小胶质细胞一样，OPCs具有星状形态并且是“平铺的”，跨越整个细胞的限定区域。 灰色和白色物质。长期以来，我们对OPC功能的认识仅限于一代成熟的 少突胶质细胞最近发表的研究对这一教条提出了挑战，这些研究表明OPCs可以 在CNS中的其他作用。事实上，一个新生的工作机构正在揭示这些细胞在细胞中的复杂作用。 炎症的背景。例如，OPCs已被证明表达细胞因子并参与细胞增殖。 外周单核细胞的募集。受伤后，OPCs可以释放IL-33，这是一种关键的警报蛋白， 免疫反应。最后，在MS的动物模型中，OPCs已被证明可以呈递抗原并应答 炎症细胞因子，这表明他们是积极的调节剂的疾病在MS。 数据表明，OPCs不是简单的旁观者，但可以参与炎症反应， CNS。我们的长期目标是阐明OPCs在中枢神经系统中的作用，重点是它们的替代免疫调节作用。 功能，以努力开发新的MS疗法。 这一建议的基础是由低密度脂蛋白受体相关的观察形成的。 蛋白-1（LRP 1）由OPCs表达，其功能是促进髓鞘和抗原交叉的吞噬作用。 演示文稿.我们的初步数据显示，在动物模型中，OPCs中LRP 1的缺失促进髓鞘再生 我们的中心假设是，在脱髓鞘过程中，OPCs交叉呈递抗原给CD 8 T细胞 以LRP 1依赖的方式，导致OPC细胞死亡并损害髓鞘再生。以强为导 证据，这一假设将通过追求三个具体目标来解决：1：评估LRP 1在 OPC介导的炎症反应，2：评估OPC抗原的药理学和遗传学操作 交叉呈递促进髓鞘修复，3：确定OPC抗原交叉呈递对T细胞的影响。 细胞功能。我们将使用脱髓鞘的体内动物模型（cuprizone和EAE）和体外培养的 OPCs和T细胞来验证我们的假设。我们的方法是创新的，因为它将利用新的小鼠品系 以及开始单细胞测序以产生OPC替代功能的新科学知识的状态 在髓鞘再生的背景下。 这项拟议中的研究意义重大，因为它将测试通过LRP 1的抗原呈递是否代表一种免疫应答。 MS和其他脱髓鞘疾病治疗开发的新靶点。从我们的研究中获得的见解 研究将导致理解OPCs如何促进炎症的根本性进展。