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.

项目概要 脊髓损伤（SCI）进展可分为急性期和慢性期。初次受伤后， 骨髓源性巨噬细胞 (BMDMɸ) 渗入受伤的中心并吞噬髓鞘碎片 成为促炎性髓磷脂巨噬细胞（Mye-Mphi）。 Mye-Mɸ 在受伤的核心积聚 密集并无限期地占据受伤区域的几乎整个震中，这将导致：1) 它们阻止轴突的进入和生长，从而抑制髓鞘再生。 2）它们失去了正常的吞噬能力 死亡细胞和细胞碎片的能力，这可能会加剧炎症微环境。 3）他们 释放炎症介质，引发炎症级联反应，阻止组织再生。我们的 数据表明，当BMDMɸ吞噬髓磷脂碎片时，其迁移潜力被直接抑制。我们 最近报道，受伤的脊髓中新形成的微血管及其内层内皮细胞​​（EC） 能够吞噬髓磷脂碎片。 ECs (Mye-ECs) 吞噬髓鞘碎片显着增加了髓磷脂碎片的沉积 细胞外基质（ECM），例如胶原蛋白和纤连蛋白，可以作为促进细胞外基质 Mye-Mphi-EC 之间的粘附相互作用并导致 Mye-Mphi 保留在受伤病变中。我们的中央 假设是，受伤核心中的 Mye-Mphi 保留是由内在和外在机制介导的， 通过 ECM 粘附促进 Mye-Mɸ 保留。拟议项目的目标是调查 Mye-Mphi 隔离的潜在机制，并确定针对 Mye-Mɸ 的治疗策略 损伤部位，这可能会恢复正常的 Mφ 功能并导致病变消退的改善。理由 拟议的研究基于初步调查，证明 Mye-Mɸ 通过以下方式“被困” 病变内内在（Mɸ产生）和外在（环境）机制的混合。我们的中央 假设将在以下具体目标中进行检验：1）研究髓磷脂碎片是否直接或通过 自分泌途径，抑制 BMDMphi 迁移能力，从而促进其病变保留； 2）确定 受伤核心中的 Mye-EC 产生的粘附性 ECM 是否会加剧 Mye-Mɸ 的保留； 3) 至 研究是否靶向 Mye-Mφ 并随后将其表型转变为修复性 表型促进组织愈合。这项研究具有创新性，因为我们提出炎症性 Mye- Mɸ 被困在受伤的脊髓病变内，导致慢性 SCI 病变，阻碍脊髓损伤的完全消退 伤害。这项工作意义重大，因为目标 1 和 2 将确定管理的基本机制 Mye-Mφ 保留，而 Aim 3 将展示解决慢性 SCI 炎症的新策略 和病变。这将对确定新的治疗策略产生积极影响 干预措施不仅可以治疗 SCI，还可以治疗其他产生髓磷脂碎片的脱髓鞘疾病。