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: 10579325
• 负责人: Yi Ren
• 金额: $ 18.64万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579325
• 关键词: Area; Attenuated; Bone Marrow; Brain; Cells; Central Nervous System; Chimera organism; Chronic; Communication; Demyelinating Diseases; Disease Progression; Exclusion; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Knowledge; Label; Lentivirus Vector; Lesion; Macrophage; Mediating; MicroRNAs; Microglia; Multiple Sclerosis; Mus; Myelin; Oligodendroglia; Paralysed; Pathologic Processes; Peripheral; Play; Recovery of Function; Regulation; Research; Role; Signal Transduction; Site; Source; Spinal Cord; Spinal cord injury; Stroke; Testing; Therapeutic; Transfection; Work; exosome; glial activation; in vivo; inhibitor; injured; innovation; migration; 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.

项目概要 慢性神经炎症在脊髓损伤 (SCI) 和 SCI 引起的继发性损伤中发挥着核心作用。 尽管外周免疫细胞如巨噬细胞（Mφ）和常驻小胶质细胞介导的 神经炎症级联反应与 SCI、外周 Mφ 和住宅的机制有关 小胶质细胞串扰以及它们的相互作用如何控制小胶质细胞介导的神经炎症仍然在很大程度上 我们的知识差距是减轻炎症引起的继发性炎症的重大障碍。 在 SCI 中，我们发现外周骨髓来源的巨噬细胞 (BMDMɸ) 会迁移到损伤部位。 受伤核心的震中，它们吞噬髓磷脂碎片，变成充满促炎髓磷脂的地方 巨噬细胞（Mye-Mphi）无限期地占据整个受伤区域的中心，相比之下，住宅区。 小胶质细胞很大程度上被排除在损伤中心之外，但与 Mye-Mphi 密切接触并仍然存在 长期激活，表明：1）BMDMφ，而不是小胶质细胞，可能是髓鞘质的主要清道夫细胞 病变中心的碎片清除，以及 2) 受伤脊柱中慢性小胶质细胞活化的原因 我们还证明髓磷脂碎片中含有大量的 microRNA。 （富含髓磷脂的 miR）和 Mye-Mφ 分泌含有丰富的富含髓磷脂的 miR 的外泌体， 与 naïve-Mφ 分泌的外泌体不同，我们进一步表明这些 Mye-Mφ 衍生的外泌体可以。 转移到小胶质细胞，促进我们的中枢小胶质细胞的额外炎症反应。 假设是，浸润的外周 BMDMφ 吞噬髓磷脂碎片和相关的 miR，并分泌外泌体 富含髓磷脂的 miR，然后转移到邻近的小胶质细胞以促进小胶质细胞介导的 我们将通过完成以下具体目标来检验我们的假设：1) 调查 外周 BMDMφ 如何调节小胶质细胞介导的神经炎症 2) 研究是否靶向。 Mye-Mφ 和小胶质细胞之间的外泌体介导的通讯影响小胶质细胞的激活。 研究具有创新性，因为外泌体是交换整合信号的独特方式，并且靶向 外泌体可能代表了一种比传统方法更有利的治疗策略 中和 SCI 中的单一炎症分子这项工作意义重大，因为我们的研究不仅可以 适用于 SCI，也适用于产生髓磷脂碎片的其他脱髓鞘疾病，如中风和多发性骨髓瘤 硬化症占瘫痪的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点。