中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1809-1817.doi: 10.4103/1673-5374.357909

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

聚(ADP-核糖)聚合酶成员14沉默不利于脊髓损伤后的功能恢复

  

  • 出版日期:2023-08-15 发布日期:2023-02-24
  • 基金资助:
    沈阳市科学技术项目(20-205-4-092)

Poly(ADP-ribose) polymerase family member 14 promotes functional recovery after spinal cord injury through regulating microglia M1/M2 polarization via STAT1/6 pathway

Ai-Hua Xu, Yang Yang, Yang Shao, Man-Yu Jiang, Yong-Xin Sun*   

  1. Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2023-08-15 Published:2023-02-24
  • Contact: Yong-Xin Sun, PhD, sunyongxin@cmu.edu.cn.
  • Supported by:
    This study was supported by the Shenyang Science and Technology Project, No. 20-205-4-092 (to AHX).

摘要:

有研究发现,一种细胞内单(ADP-核糖基)转移酶—聚(ADP-核糖)聚合酶成员14(PARP14)可促进脑卒中后神经功能的恢复,但其在脊髓损伤中的功能尚不清楚。(1)为研究这个问题,实验首先建立了T10脊髓挫伤C57BL/6J小鼠模型,并在损伤后立即在损伤部位前后约1 mm处注射携带PARP14 shRNA的慢病毒以沉默PARP14。结果发现,脊髓损伤后,脊髓组织中PARP14表达上调,而敲低PARP14可加重脊髓损伤后的运动功能障碍,并伴随着显著的神经元丢失、严重的神经炎症以及轻微的骨丢失。此外,脊髓损伤后小胶质细胞中的PARP14也升高,PARP14敲低可激活脊髓组织中的小胶质细胞,并促进M2极化小胶质细胞(抗炎表型)向M1极化小胶质细胞(促炎表型)转变,这可能与信号转导和转录激活因子1/6通路有关。(2)接下来以脂多糖/干扰素γ诱导小胶质细胞M1 极化或以白细胞介素4诱导小胶质细胞M2极化来进行体外实验。结果表明,PARP14敲低可促进小胶质细胞的M1极化,同时激活了STAT1通路;而PARP14过表达则使小胶质细胞更容易发生M2极化,同时STAT6通路被激活。(3)综上可见,敲低PARP14通过STAT1/6通路调节小胶质细胞的表型转化,可促进脊髓损伤后神经功能的恢复。

https://orcid.org/0000-0002-1166-1627 (Yong-Xin Sun)

关键词: 脊髓损伤, PARP14, 基因沉默, 小胶质细胞, M1极化, M2极化, STAT1通路, STAT6通路, 细胞凋亡, 神经炎症

Abstract: Poly(ADP-ribose)polymerase family member 14 (PARP14), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis, severe neuroinflammation, and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization, accompanied by activation of the STAT1 pathway. In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway. In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway.

Key words: apoptosis, M1 polarization, M2 polarization, microglia, neuroinflammation, PARP14, silencing, spinal cord injury, STAT1 pathway, STAT6 pathway