Emerging role of exosomes derived from peripheral immune cells in regulation of neuroinflammation in response to neural injury

外周免疫细胞衍生的外泌体在调节神经损伤反应中的神经炎症中的新作用

• 批准号: 10450269
• 负责人: Yi Ren
• 金额: $ 22.5万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450269
• 关键词: Area; Attenuated; Bone Marrow; Brain; Cells; Chimera organism; Chronic; Communication; Demyelinating Diseases; Disease Progression; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Knowledge; Label; Lentivirus Vector; Lesion; Mediating; MicroRNAs; Microglia; Multiple Sclerosis; Mus; Myelin; Neuraxis; Oligodendroglia; Paralysed; Pathologic Processes; Peripheral; Play; Recovery of Function; Regulation; Research; Role; Signal Transduction; Site; Source; Spinal Cord; Spinal cord injury; Stroke; Testing; Therapeutic; Work; base; exosome; in vivo; inhibitor; injured; innovation; macrophage; nerve injury; neuroinflammation; new therapeutic target; response

Project Summary Chronic neuroinflammation plays a central role in spinal cord injury (SCI) and SCI-induced secondary damage. Although peripheral immune cells such as macrophages (Mφ) and the resident microglia-mediated neuroinflammatory cascade have been implicated in SCI, the mechanisms of peripheral Mφ and residential microglia cross talk and how their interaction controls microglia-mediated neuroinflammation remains largely unknown. This gap in our knowledge is a significant barrier to mitigating inflammation-induced secondary damage in SCI. We have shown that peripheral bone marrow-derived macrophages (BMDMɸ) migrate to the epicenter of the injured core, where they engulf myelin debris to become pro-inflammatory myelin-laden macrophages (Mye-Mϕ), which occupy the entire epicenter of the injured area indefinitely. In contrast, residential microglia are largely excluded from the injury epicenter, but are in close contact with Mye-Mϕ and remain chronically activated, suggesting that: 1) BMDMφ, not microglia, may be the major scavenger cells for myelin debris clearance from the lesion center, and 2) the cause of chronic microglial activation in the injured spinal cord is constantly present. We also demonstrated that myelin debris contains significant quantities of microRNAs (myelin-enriched miRs) and Mye-Mφ secrete exosomes that contain abundant myelin-enriched miRs, which are distinct from naïve-Mφ secreted exosomes. We further showed that these Mye-Mφ-derived exosomes can transfer to microglia, promoting additional inflammatory responses in microglia. Consequently, our central hypothesis is that infiltrated peripheral BMDMφ engulf myelin debris and associated miRs and secrete exosomal myelin-enriched miRs, which are then transferred to adjacent microglia to promote microglia-mediated neuroinflammation in SCI. We will test our hypothesis by completing the following specific aims: 1) Investigate how peripheral BMDMφ regulate microglia-mediated neuroinflammation. 2) Investigate whether targeting exosome-mediated communication between Mye-Mφ and microglia influences microglial activation. This research is innovative because exosomes are a unique way of exchanging integrated signals, and targeting exosomes may represent a therapeutic strategy more advantageous than classical approaches aimed at neutralizing single inflammatory molecules in SCI. This work is significant because our study can not only be applied to SCI but also to other demyelinating diseases that generate myelin debris such as stroke and multiple sclerosis, which account for 80% of the sources of paralysis. Our research will have the positive impact of generating novel therapeutic targets for SCI treatment.

项目摘要 慢性神经炎症在脊髓损伤（SCI）和SCI诱导的继发性损伤中起着核心作用。 虽然外周免疫球（例如巨噬细胞（Mφ）和驻留小胶质细胞介导的） 在SCI，外围Mφ的机制和居民中，神经炎症性级联反应已隐含 小胶质细胞交谈及其相互作用如何控制小胶质细胞介导的神经炎症仍然很大程度上仍然存在 未知。我们所知的差距是减轻注射诱导的次级的重大障碍 科学损害。我们已经表明，外围骨髓衍生的巨噬细胞（BMDMɸ）迁移到 受伤的核心的中心，它们吞噬了髓磷脂碎屑，成为促炎性髓磷脂 巨噬细胞（mye-mϕ），无限期地占据了受伤区域的整个中心。相反，居民 小胶质细胞在很大程度上被排除在损伤的中心之外，但与Mye-mϕ密切接触 长期激活的表明：1）BMDMφ，而不是小胶质细胞可能是髓磷脂的主要清除剂细胞 病变中心的碎屑清除和2）受伤的脊柱中慢性小胶质细胞激活的原因 电线不断存在。我们还证明髓磷脂碎屑含有大量的microRNA （髓磷脂富集的mirs）和含有丰富髓磷脂的mirs的肌电蛋白质外泌体 与幼稚的分泌外泌体不同。我们进一步表明，这些Mye-mφ衍生的外泌体可以 转移至小胶质细胞，促进小胶质细胞中的其他炎症反应。因此，我们的中心 假设是浸润的周围BMDMφ吞噬髓磷脂碎片和相关的mir和秘密外泌体 髓磷脂富含miRS，然后将其转移到相邻的小胶质细胞中，以促进小胶质细胞介导 Sci中的神经炎症。我们将通过完成以下特定目的来检验我们的假设：1）调查 周围BMDMφ如何调节小胶质细胞介导的神经炎症。 2）调查是否针对 外泌体介导的MyE-Mφ和小胶质细胞之间的通信会影响小胶质细胞激活。这 研究具有创新性，因为外泌体是交换综合信号和定位的独特方法 外泌体可能代表的治疗策略比针对的经典方法更有优势 中和Sci中的单个炎症分子。这项工作很重要，因为我们的研究不仅可以 适用于SCI，也适用于其他脱髓鞘疾病，产生髓鞘碎片，例如中风和多个 硬化症，占瘫痪来源的80％。我们的研究将产生积极的影响 为SCI治疗产生新的治疗靶标。