miRNA Regulation of Macrophages after Spinal Cord Injury

描述（由申请人提供）：脊髓损伤（SCI）后，“M1”（促炎）和“M2”（抗炎）巨噬细胞聚集在病变部位。M1巨噬细胞，引起神经毒性和阻碍神经再生，持续在SCI病变。相反，支持轴突生长且无神经毒性的M2巨噬细胞在几天后消失。M2巨噬细胞的这种进行性“损失”被认为是由于新活化的小胶质细胞和浸润的单核细胞在急性SCI环境中响应促炎性线索时转化为M1细胞。到目前为止，这种现象阻碍了利用M2巨噬细胞的再生能力来改善SCI恢复的尝试。因此，积极寻求在高度炎症性SCI环境中抑制M1和增强M2巨噬细胞的治疗策略。我们最近发现了M1分化所需的特定microRNA（miRNA）。miRNA是转录后调节基因表达网络的小RNA，有助于细胞分化和谱系选择。我们预测，这种miRNA的特异性调节将降低SCI后M1/M2巨噬细胞的比例，从而提高SCI后组织修复的效率和程度。这一假设将在SCI的体内模型中进行测试，使用缺乏这种特定mRNA的小鼠，并开发出一种用特定miRNA抑制剂调节巨噬细胞表型的药理学策略。由于可以操纵miRNA来治疗人类疾病，这些研究将为开发有前途的新疗法提供基础。此外，了解这种特定的miRNA如何通过调节M1/M2平衡来控制炎症，将对调节其他疾病（如动脉粥样硬化，伤口愈合和癌症）中巨噬细胞介导的炎症（或免疫抑制）具有重要意义。 公共卫生相关性：这些研究探讨了小RNA miR-155在脊髓损伤炎症、病理学和功能恢复中的作用。将在脊髓损伤的啮齿动物模型中评估巨噬细胞靶向的miR-155损失在控制炎症和增强神经再生中的作用。这些研究可能会影响脊髓损伤和其他疾病的治疗，如动脉粥样硬化，伤口愈合和癌症。

DESCRIPTION (provided by applicant): After spinal cord injury (SCI), "M1" (pro-inflammatory) and "M2" (anti-inflammatory) macrophages populate the lesion site. M1 macrophages, which cause neurotoxicity and hamper neuroregeneration, persist in SCI lesions. In contrast, M2 macrophages, which support axon growth and are not neurotoxic, disappear after a few days. This progressive "loss" of M2 macrophages is thought to be due to the conversion of newly activated microglia and infiltrating monocytes into M1 cells as they respond to pro- inflammatory cues in the acute SCI environment. This phenomenon has so far impeded attempts to harness the regenerative power of M2 macrophages to improve SCI recovery. Therefore, therapeutic strategies that suppress M1 and enhance M2 macrophages in the highly inflammatory SCI environment are actively sought. We have recently identified a specific microRNA (miRNA) required for M1 differentiation. miRNA are small RNAs that post-transcriptionally regulate gene expression networks, contributing to cell differentiation and lineage choice. We predict that specific modulation of this miRNA will reduce the ratio of M1/M2 macrophages after SCI, thereby improving the efficiency and extent of tissue repair after SCI. This hypothesis will be tested in an in vivo model of SCI, using mice deficient for this specific mRNA, and developing a pharmacologic strategy to modulate macrophage phenotype with specific miRNA inhibitors. Since miRNA can be manipulated to treat human disease, these studies will provide the basis for development of promising new therapies. In addition, understanding how this specific miRNA controls inflammation through regulation of the M1/M2 balance will have important implications to regulation of macrophage-mediated inflammation (or immune suppression) in other conditions, such as atherosclerosis, wound healing and cancer. PUBLIC HEALTH RELEVANCE: These studies investigate the role of the small RNA miR-155 in spinal cord injury inflammation, pathology and functional recovery. The effects of macrophage-targeted miR-155 loss in control of inflammation and enhancement of neuroregeneration will be assessed in a rodent model of spinal cord injury. These studies will likely impact therapies for spinal cord injury and other conditions such as atherosclerosis, wound healing and cancer.