Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core

探索损伤脊髓病变核心中促炎髓磷脂巨噬细胞保留的治疗机制

• 批准号: 10419193
• 负责人: Yi Ren
• 金额: $ 37.9万
• 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: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419193
• 关键词: Acute; Adhesions; Adhesives; Affect; Apoptotic; Area; Bone Marrow; Cells; Chemotactic Factors; Chronic; Chronic Phase; Collagen; Data; Demyelinating Diseases; Deposition; Endothelial Cells; Extracellular Matrix; Fibronectins; Generations; Goals; Human; Immune; In Situ; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Knowledge; Lead; Lesion; Lipids; Mediating; Myelin; Necrosis; Nerve Regeneration; Outcome; Pathway interactions; Phagocytes; Phase; Phenotype; Plant Roots; Process; Public Health; Publications; Recovery of Function; Regulation; Reporting; Research; Resolution; Signal Transduction; Site; Spinal; Spinal Cord Lesions; Spinal Injuries; Spinal cord injury; Tail; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States National Institutes of Health; Work; autocrine; axon growth; base; density; disability; healing; improved; injured; innovation; macrophage; migration; nerve stem cell; neural growth; neuroinflammation; new therapeutic target; novel; novel strategies; novel therapeutic intervention; prevent; relating to nervous system; remyelination; tissue regeneration; treatment strategy; uptake

PROJECT SUMMARY Spinal cord injury (SCI) progression can be divided into acute and chronic phases. Following the primary injury, bone marrow-derived macrophages (BMDMɸ) infiltrate to the injured epicenter where they engulf myelin debris to become proinflammatory myelin-laden macrophages (Mye-Mϕ). Mye-Mɸ accumulate in the injured core densely and occupy almost entire epicenter of injured area indefinitely, which would consequently result in: 1) They prevent the entry and growth of axons, which inhibits remyelination. 2) They lose their normal phagocytic capacity for dead cells and cellular debris, which may exacerbate the inflammatory microenvironment. 3) They release inflammatory mediators, which trigger an inflammatory cascade that prevents tissue regeneration. Our data indicated that the migratory potential of BMDMɸ is directly suppressed when they engulf myelin debris. We resently reported that newly formed microvessels and their lining endothelial cells (ECs) in the injured cord are able to engulf myelin debris. Myelin debris engulfment by ECs (Mye-ECs) significantly increased deposition of extracellular matrices (ECM) such as collagen and fibronectin which may serve as extrinsic factor to promote the adhesive interaction between Mye-Mϕ-ECs and lead to Mye-Mϕ retention in the injured lesion. Our central hypothesis is that Mye-Mϕ retention in the injured core is mediated by intrinsic and extrinsic mechanisms which promote Mye-Mɸ retention through ECM adhesion. The objective of the proposed project is to investigate the underlying mechanisms of Mye-Mϕ sequestration and identify treatment strategies that target Mye-Mɸ in the injury site, which may restore normal Mφ functions and lead to improvements in lesion resolution. The rationale for the proposed research is based on preliminary investigations that demonstrate Mye-Mɸ become ‘trapped’ via a mix of intrinsic (Mɸ produced) and extrinsic (environmental) mechanisms within the lesion. Our central hypothesis will be tested in the following specific aims: 1) To study whether myelin debris, either directly or via autocrine pathways, inhibits BMDMϕ migration ability which promotes their lesion retention; 2) To determine whether adhesive ECM produced by Mye-ECs in the injured core aggravates Mye-Mɸ retention; and 3) To investigate whether targeting Mye-Mφ and subsequently switching their phenotype toward a reparative phenotype promotes tissue healing. This research is innovative because we propose that inflammatory Mye- Mɸ trapped within the injured spinal cord lesion contribute to the chronic SCI lesion, preventing full resolution of the injury. This work is significant because Aims 1 and 2 will identify the underlying mechanisms governing Mye-Mφ retention, while Aim 3 will demonstrate novel strategies for the resolution of chronic SCI inflammation and lesions. This will have the positive impact of identifying novel therapeutic strategies for therapeutic interventions not only to treat SCI but also to other demyelinating disorders that generate myelin debris.

项目摘要 脊髓损伤（SCI）的进展可以分为急性和慢性相。主要受伤后， 骨髓来源的巨噬细胞（BMDMɸ）渗入受伤的震中，它们吞噬了髓磷脂 Mye-mɸ积聚在受伤的核心中 密集并占据了几乎整个受伤区域的震中，因此会导致：1） 它们防止了轴突的进入和生长，从而抑制了再生。 2）他们失去了正常的吞噬性 死细胞和细胞碎片的能力，这可能加剧炎症微环境。 3）他们 释放炎症介质，这会触发阻止组织再生的炎症级联反应。我们的 数据表明，当BMDMɸ吞噬髓磷脂碎片时，它们的迁移潜力被直接抑制。我们 非常详细地报道了新形成的微血管及其衬里的内皮细胞（EC）是受伤的绳索 ECS（Mye-Ecs）吞噬髓磷脂碎片显着增加了的沉积 细胞外基质（ECM），例如胶原蛋白和纤连蛋白，可以作为促进的外部因素 MyE-Mϕ-EC之间的粘合剂相互作用，并导致受伤病变中的MyE-Mϕ保留。我们的中心 假设是在受伤的核心中保留了MyE-mϕ，是由内在和外在机制介导的，这些机制 通过ECM粘合剂促进Mye-Mɸ保留。拟议项目的目的是调查 MYE-Mϕ隔离的基本机制，并确定针对Mye-Mɸ的治疗策略 损伤部位可能会恢复正常的Mφ功能并导致病变分辨率改善。理由 拟议的研究是基于初步调查，证明我是通过 病变内的内在（Mɸ产生）和外在（环境）机制的混合物。我们的中心 假设将在以下特定目的中进行检验：1）研究是直接还是通过直接或通过 自分泌途径，抑制了促进其病变保留率的BMDM移迁移能力； 2）确定 MyE-EC在受伤的核心中产生的粘合剂ECM是否会加剧Mye-Mɸ保留；和3）到 调查靶向my-mφ并随后将其表型切换为修复 表型促进组织愈合。这项研究具有创新性，因为我们建议炎症性mye- 被困在受伤的脊髓病变中 受伤。这项工作很重要，因为目标1和2将确定管理的基本机制 MyE-Mφ保留，而AIM 3将展示慢性科幻注射的新策略 和病变。这将具有确定新型治疗策略的积极影响 干预措施不仅要治疗SCI，还要处理其他产生髓磷脂碎片的脱髓鞘疾病。