Kentucky Spinal Cord Injury Research Center, 511 S. Floyd St., Rm. 616A, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Neurobiol Dis. 2011 Apr;42(1):21-34. doi: 10.1016/j.nbd.2010.12.010. Epub 2010 Dec 17.
Recent data have implicated thrombospondin-1 (TSP-1) signaling in the acute neuropathological events that occur in microvascular endothelial cells (ECs) following spinal cord injury (SCI) (Benton et al., 2008b). We hypothesized that deletion of TSP-1 or its receptor CD47 would reduce these pathological events following SCI. CD47 is expressed in a variety of tissues, including vascular ECs and neutrophils. CD47 binds to TSP-1 and inhibits angiogenesis. CD47 also binds to the signal regulatory protein (SIRP)α and facilitates neutrophil diapedesis across ECs to sites of injury. After contusive SCI, TSP-1(-/-) mice did not show functional improvement compared to wildtype (WT) mice. CD47(-/-) mice, however, exhibited functional locomotor improvements and greater white matter sparing. Whereas targeted deletion of either CD47 or TSP-1 improved acute epicenter vascularity in contused mice, only CD47 deletion reduced neutrophil diapedesis and increased microvascular perfusion. An ex vivo model of the CNS microvasculature revealed that CD47(-/-)-derived microvessels (MVs) prominently exhibit adherent WT or CD47(-/-) neutrophils on the endothelial lumen, whereas WT-derived MVs do not. This implicates a defect in diapedesis mediated by the loss of CD47 expression on ECs. In vitro transmigration assays confirmed the role of SIRPα in neutrophil diapedesis through EC monolayers. We conclude that CD47 deletion modestly, but significantly, improves functional recovery from SCI via an increase in vascular patency and a reduction of SIRPα-mediated neutrophil diapedesis, rather than the abrogation of TSP-1-mediated anti-angiogenic signaling.
最近的数据表明，血小板反应蛋白-1（TSP-1）信号在脊髓损伤（SCI）后微血管内皮细胞（EC）中发生的急性神经病理事件中起作用（Benton 等人，2008b）。我们假设删除 TSP-1 或其受体 CD47 会减少 SCI 后的这些病理事件。CD47 在多种组织中表达，包括血管 EC 和中性粒细胞。CD47 与 TSP-1 结合并抑制血管生成。CD47 还与信号调节蛋白（SIRP）α结合，促进中性粒细胞穿过 EC 到损伤部位。在挫伤性 SCI 后，与野生型（WT）小鼠相比，TSP-1（-/-）小鼠没有表现出功能改善。然而，CD47（-/-）小鼠表现出运动功能的改善和更多的白质保留。虽然靶向删除 CD47 或 TSP-1 都改善了挫伤小鼠的急性中心血管密度，但只有 CD47 缺失减少了中性粒细胞穿出并增加了微血管灌注。中枢神经系统微血管的体外模型显示，CD47（-/-）衍生的微血管（MVs）在血管内腔上明显表现出附着的 WT 或 CD47（-/-）中性粒细胞，而 WT 衍生的 MVs 则没有。这表明 CD47 在 EC 上的表达缺失会导致穿出缺陷。体外迁移测定证实了 SIRPα 在通过 EC 单层的中性粒细胞穿出中的作用。我们得出结论，CD47 缺失适度但显著地通过增加血管通透性和减少 SIRPα 介导的中性粒细胞穿出，而不是通过阻断 TSP-1 介导的抗血管生成信号来改善 SCI 的功能恢复。
