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

项目摘要 慢性神经炎在脊髓损伤(SCI)及继发性损伤中起重要作用。 尽管巨噬细胞(Mφ)等外周免疫细胞和常驻的小胶质细胞介导的 神经炎性级联反应参与了脊髓损伤、外周Mφ和住宅的发病机制 小胶质细胞串扰及其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存在 未知。我们知识上的这种差距是减轻炎症诱导的继发性疾病的一个重要障碍 在SCI中造成的损害。我们已经证明，外周骨髓来源的巨噬细胞(BMDMɸ)迁移到 位于受损核心的震中，在那里它们吞噬髓鞘碎片，成为携带促炎症髓鞘的 巨噬细胞(MYE-Mϕ)，无限期地占据损伤区域的整个震中。相比之下，住宅 小胶质细胞很大程度上被排除在损伤中心之外，但与Mye-Mϕ密切接触并保留 慢性激活，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 从损伤中心清除碎片，以及2)损伤脊髓中慢性小胶质细胞激活的原因 电源线一直存在。我们还证明了髓鞘碎片中含有大量的microRNA。 (富含髓鞘的miRs)和MYE-Mφ分泌的外体含有丰富的富含髓鞘的miRs， 不同于NAYVE-Mφ分泌的外切体。我们进一步表明，这些由MYE-Mφ衍生的外体可以 转移到小胶质细胞，促进小胶质细胞的额外炎症反应。因此，我们的中央 假说是浸润性的外周BMDMφ吞噬髓鞘碎片和相关的MIR和分泌外体 富含髓鞘的miRs，然后转移到邻近的小胶质细胞，促进小胶质细胞介导的 脊髓损伤中的神经炎症。我们将通过完成以下具体目标来验证我们的假设：1)调查 外周BMDMφ如何调节小胶质细胞介导的神经炎症。2)调查目标是否 外切体介导的Mye-Mφ和小胶质细胞之间的通讯影响小胶质细胞的激活。这 研究具有创新性，因为外显体是一种交换集成信号和靶向的独特方式 Exosome可能代表了一种比传统方法更有利的治疗策略 中和脊髓损伤中的单个炎症分子。这项工作意义重大，因为我们的研究不仅可以 适用于脊髓损伤，但也适用于产生髓鞘碎片的其他脱髓鞘疾病，如中风和多发性 硬化症，占瘫痪来源的80%。我们的研究将对 为脊髓损伤治疗产生新的治疗靶点。

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.