Spine Center, Department of Orthopaedics, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China.
Spine Center, Department of Orthopaedics, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China.
Cell Signal. 2024 Feb;114:110978. doi: 10.1016/j.cellsig.2023.110978. Epub 2023 Nov 14.
Spinal cord injury (SCI) is a devastating disorder and a leading cause of disability in adults worldwide. Multiple studies have reported the upregulation of programmed cell death 1 (PD-1) following SCI. However, the underlying mechanism of PD-1 deficiency in SCI is not well established. Therefore, we aimed to investigate the role and potential mechanism of PD-1 in SCI pathogenesis. PD-1 Knockout (KO) SCI mouse model was established, and PD-1 expression was evaluated in tissue samples by western blot assay. We then used a series of function gain-and-loss assays to determine the role of PD-1 in SCI pathogenesis. Moreover, mechanistic assays were performed to explore the association between PD-1, neuron-glia antigen-2 (NG2) glia cells, and miR-23b-5p and then investigated the involved signaling pathway. Results illustrated that PD-1 deficiency enhanced the inflammatory response, neuron loss, and functional impairment induced by SCI. We found that NG2 glia depletion aggravated inflammation, reduced neural survival, and suppressed locomotor recovery in murine SCI model. Further analysis indicated that NG2 cells were increased in the spinal cord of SCI mice, and PD-1 deficiency increased the number of NG2 cells by activating the Nogo receptor/ras homolog family member A/Rho kinase (NgR/RhoA/ROCK) signaling. Mechanistically, miR-23b-5p was identified as the negative regulator of PD-1 in NG2 glia. MiR-23b-5p deficiency reduced the expression of inflammatory cytokines, enhanced neural survival, and promoted locomotor recovery in SCI mice, which was counteracted by PD-1 deficiency. In conclusion, PD-1 deficiency exacerbates SCI in vivo by regulating reprogramming of NG2 glia and activating the NgR/RhoA/ROCK signaling.
脊髓损伤 (SCI) 是一种破坏性疾病，也是全球成年人残疾的主要原因。多项研究报告称，SCI 后程序性细胞死亡 1 (PD-1) 的表达上调。然而，SCI 中 PD-1 缺乏的潜在机制尚未完全确定。因此，我们旨在研究 PD-1 在 SCI 发病机制中的作用和潜在机制。建立了 PD-1 敲除 (KO) SCI 小鼠模型，通过 Western blot 检测组织样本中 PD-1 的表达。然后，我们使用一系列功能增益和缺失实验来确定 PD-1 在 SCI 发病机制中的作用。此外，还进行了机制实验来探讨 PD-1、神经元-神经胶质抗原-2 (NG2) 神经胶质细胞和 miR-23b-5p 之间的关联，然后研究了涉及的信号通路。结果表明，PD-1 缺乏增强了 SCI 引起的炎症反应、神经元丢失和功能障碍。我们发现，NG2 胶质细胞耗竭加重了炎症反应，减少了神经存活，并抑制了 SCI 小鼠的运动功能恢复。进一步分析表明，SCI 小鼠脊髓中 NG2 细胞增加，PD-1 缺乏通过激活 Nogo 受体/ras 同源家族成员 A/Rho 激酶 (NgR/RhoA/ROCK) 信号增加 NG2 细胞数量。机制上，miR-23b-5p 被鉴定为 NG2 胶质细胞中 PD-1 的负调节因子。miR-23b-5p 缺乏减少了炎症细胞因子的表达，增强了神经存活，并促进了 SCI 小鼠的运动功能恢复，而 PD-1 缺乏则拮抗了这一作用。总之，PD-1 缺乏通过调节 NG2 胶质细胞的重编程并激活 NgR/RhoA/ROCK 信号来加重体内 SCI。
