The effects of human immunoglobulin G on enhancing tissue protection and neurobehavioral recovery after traumatic cervical spinal cord injury are mediated through the neurovascular unit
The effects of human immunoglobulin G on enhancing tissue protection and neurobehavioral recovery after traumatic cervical spinal cord injury are mediated through the neurovascular unit
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DOI：
10.1186/s12974-019-1518-0
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发表时间：
2019-07-09
影响因子：
9.3
通讯作者：
Fehlings, Michael G.
中科院分区：
文献类型：
--
作者：
Chio, Jonathon Chon Teng;Wang, Jian;Fehlings, Michael G.
背景脊髓损伤（spinal cord injury，SCI）是一种有效的治疗方法。血-脊髓屏障由周细胞、星形胶质细胞和内皮细胞组成，统称为神经血管单位。这些细胞通过表达紧密连接蛋白来支持脊髓内稳态。脊髓的物理创伤破坏了屏障，这通过在涉及免疫细胞粘附的过程中促进免疫细胞迁移到受损部位而导致神经炎症。免疫抑制策略，包括甲基强的松龙（MPSS），已被研究用于治疗SCI。然而，尽管取得了一些成功，但MPSS有可能增加患者对伤口感染的易感性和受损的伤口愈合。因此，免疫调节可能是比免疫抑制更有吸引力的方法。静脉注射人免疫球蛋白G（hIgG）已被批准用于调节某些疾病（包括格林-巴利综合征）中的神经炎症，在实验性SCI的背景下显示出前景，方法成年雌性Wistar大鼠在C7-T1节段遭受中度-重度夹压损伤（35 g），并随机接受单次静脉内（IV）在SCI后15分钟推注hIgG（0.02、0.2、0.4、1、2g/kg）、MPSS（0.03g/kg）或对照缓冲液。在24小时和6周后SCI，分子，组织学和神经行为hIgG的影响进行了analysed.ResultsAt 24小时后，人免疫球蛋白G共定位与脊髓周细胞，星形胶质细胞和血管。hIgG（2g/kg）通过增加紧密连接蛋白的表达和减少炎性酶的表达来保护SCI后的脊髓神经血管。血管完整性的改善与脊髓炎症的变化相关。有趣的是，hIgG（2g/kg）增加炎性细胞因子的血清表达，并且与脊髓血管细胞粘附分子-1（免疫细胞用于进入发炎组织的蛋白质）共定位（不降低蛋白质表达）。SCI后6周，hIgG（2g/kg）的急性分子益处导致更好的组织保护、功能性血流和神经行为恢复。重要的是，hIgG（2g/kg）的效果上级对照缓冲液和hIgG（0.4g/kg），并与MPSS（0.03g/kg）相当。结论hIgG（2g/kg）是一种有前途的治疗方法，以减轻继发性病理损伤，通过拮抗免疫细胞浸润的神经血管单位的水平。
BackgroundSpinal cord injury (SCI) is a condition with few effective treatment options. The blood-spinal cord barrier consists of pericytes, astrocytes, and endothelial cells, which are collectively termed the neurovascular unit. These cells support spinal cord homeostasis by expressing tight junction proteins. Physical trauma to the spinal cord disrupts the barrier, which leads to neuroinflammation by facilitating immune cell migration to the damaged site in a process involving immune cell adhesion. Immunosuppressive strategies, including methylprednisolone (MPSS), have been investigated to treat SCI. However, despite some success, MPSS has the potential to increase a patient's susceptibility to wound infection and impaired wound healing. Hence, immunomodulation may be a more attractive approach than immunosuppression. Approved for modulating neuroinflammation in certain disorders, including Guillain-Barre syndrome, intravenous administration of human immunoglobulin G (hIgG) has shown promise in the setting of experimental SCI, though the optimal dose and mechanism of action remain undetermined.MethodsFemale adult Wistar rats were subjected to moderate-severe clip compression injury (35g) at the C7-T1 level and randomized to receive a single intravenous (IV) bolus of hIgG (0.02, 0.2, 0.4, 1, 2g/kg), MPSS (0.03g/kg), or control buffer at 15min post-SCI. At 24h and 6weeks post-SCI, molecular, histological, and neurobehavioral effects of hIgG were analyzed.ResultsAt 24h post-injury, human immunoglobulin G co-localized with spinal cord pericytes, astrocytes, and vessels. hIgG (2g/kg) protected the spinal cord neurovasculature after SCI by increasing tight junction protein expression and reducing inflammatory enzyme expression. Improvements in vascular integrity were associated with changes in spinal cord inflammation. Interestingly, hIgG (2g/kg) increased serum expression of inflammatory cytokines and co-localized (without decreasing protein expression) with spinal cord vascular cell adhesion molecule-1, a protein used by immune cells to enter into inflamed tissue. Acute molecular benefits of hIgG (2g/kg) led to greater tissue preservation, functional blood flow, and neurobehavioral recovery at 6weeks post-SCI. Importantly, the effects of hIgG (2g/kg) were superior to control buffer and hIgG (0.4g/kg), and comparable with MPSS (0.03g/kg).ConclusionshIgG (2g/kg) is a promising therapeutic approach to mitigate secondary pathology in SCI through antagonizing immune cell infiltration at the level of the neurovascular unit.