miRNA Regulation of Macrophages after Spinal Cord Injury

描述(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。造成神经毒性和阻碍神经再生的M1巨噬细胞持续存在于脊髓损伤中。相比之下，M2巨噬细胞支持轴突生长，并且没有神经毒性，几天后就会消失。M2巨噬细胞的这种渐进性“丧失”被认为是由于在急性脊髓损伤环境中对促炎信号做出反应时，新激活的小胶质细胞和渗入的单核细胞转化为M1细胞所致。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脊髓损伤恢复的尝试。因此，在高度炎症的脊髓损伤环境中，积极寻求抑制M1和增强M2巨噬细胞的治疗策略。我们最近发现了M1分化所需的一种特定的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的特异性调控将降低脊髓损伤后M1/M2巨噬细胞的比例，从而提高脊髓损伤后组织修复的效率和程度。这一假设将在脊髓损伤的体内模型中得到验证，使用缺乏这种特定mRNA的小鼠，并开发一种用特定的miRNA抑制剂调节巨噬细胞表型的药理学策略。由于miRNA可以被操纵来治疗人类疾病，这些研究将为开发有前景的新疗法提供基础。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，将对调节其他条件下的巨噬细胞介导的炎症(或免疫抑制)具有重要意义，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.