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

项目摘要 慢性神经炎症在脊髓损伤（SCI）及其继发性损伤中起着重要作用。 虽然外周免疫细胞如巨噬细胞（Mφ）和常驻小胶质细胞介导的 神经炎性级联反应与SCI有关，外周Mφ和住宅M φ的机制与SCI有关。 小胶质细胞的串扰以及它们之间的相互作用如何控制小胶质细胞介导的神经炎症在很大程度上仍然是 未知我们知识上的这一差距是减轻炎症诱导的继发性炎症的一个重要障碍。 SCI损伤我们已经证明外周骨髓源性巨噬细胞（BMDM）迁移到 损伤核心的震中，在那里它们吞噬髓鞘碎片，成为促炎性髓鞘负载 巨噬细胞（Mye-M），其无限期地占据受伤区域的整个震中。相比之下，住宅 小胶质细胞在很大程度上被排除在损伤中心之外，但与Mye-M神经元密切接触， 提示：1）BMDMφ，而不是小胶质细胞，可能是髓鞘的主要清道夫细胞 碎片从病变中心清除，和2）在受伤的脊髓中慢性小胶质细胞活化的原因 CORD一直存在。我们还证明，髓鞘碎片含有大量的microRNA， （富含髓鞘的miR）和Mye-Mφ分泌含有丰富的富含髓鞘的miR的外泌体， 与幼稚M φ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，促进小胶质细胞中的额外炎症反应。因此，我们的中央 假设浸润外周BMDMφ吞噬髓磷脂碎片和相关的miR并分泌外泌体， 富含髓鞘的miRs，然后转移到邻近的小胶质细胞以促进小胶质细胞介导的 SCI的神经炎症。我们将通过完成以下具体目标来测试我们的假设：1）调查 外周BMDMφ如何调节小胶质细胞介导神经炎症2)调查是否针对 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活化。这 研究是创新的，因为外泌体是一种独特的交换整合信号的方式， 外泌体可能代表了一种比经典方法更有利的治疗策略， 中和SCI中的单个炎症分子。这项工作意义重大，因为我们的研究不仅可以 适用于SCI，但也适用于其他产生髓鞘碎片的脱髓鞘疾病，如中风和多发性硬化症。 硬化症，占瘫痪来源的80%。我们的研究将产生积极的影响 产生用于SCI治疗的新的治疗靶点。

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.