Zeng Fanzhuo, Chen Anqi, Chen Wei, Cheng Shuai, Lin Sen, Mei Rongcheng, Mei Xifan
Department of Orthopedics, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, Hubei, China.
Department of Orthopedics, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121002, Liaoning, China.
Heliyon. 2024 Aug 16;10(17):e36488. doi: 10.1016/j.heliyon.2024.e36488. eCollection 2024 Sep 15.
Spinal cord injury (SCI) is a serious and difficult to treat traumatic disease of the central nervous system. Spinal cord injury causes a variety of detrimental effects, including neuroinflammation and ferroptosis, leading to chronic functional impairment and death. Recent studies have shown that microglia/macrophages (M/Ms) at the injury site remain primarily in the pro-inflammatory state, which is detrimental to recovery. However, information on the factors behind pro-inflammatory polarization skew in the injured spinal cord remains unclear. In this study, we found that Tumor Necrosis Factor-α(TNF-α) ablation protected after SCI by suppressing neuroinflammation and ferroptosis. Though using TNF-α knock out mice (TNF-/-), we induced downregulation of TNF-α in M/Ms and further investigated its effect on SCI outcome. In TNF-/- mice, significant behavioral improvements were observed as early as 7 days after injury. We showed that TNF-α inhibition promote injury-mediated M/Ms polarization from pro-inflammatory to anti-inflammatory phenotype in vivo. Furthermore, accumulated iron in M/Ms after SCI increased the expression of TNF-α and the population of M/Ms to pro-inflammatory phenotype. Moreover, zinc supplement reduced the secondary damage caused by iron overload. In conclusion, we found that knock out of TNF-α promotes recovery of motor function after spinal cord injury in mice by inhibiting ferroptosis and promoting the shift of macrophages to an anti-inflammatory phenotype, indicating that there is great potential for this therapy to SCI.
脊髓损伤（SCI）是一种严重且难以治疗的中枢神经系统创伤性疾病。脊髓损伤会导致多种有害影响，包括神经炎症和铁死亡，进而导致慢性功能障碍和死亡。最近的研究表明，损伤部位的小胶质细胞/巨噬细胞（M/Ms）主要保持促炎状态，这对恢复不利。然而，关于脊髓损伤后促炎极化偏向背后的因素仍不清楚。在本研究中，我们发现肿瘤坏死因子-α（TNF-α）缺失通过抑制神经炎症和铁死亡在脊髓损伤后起到保护作用。通过使用TNF-α基因敲除小鼠（TNF-/-），我们诱导M/Ms中TNF-α的下调，并进一步研究其对脊髓损伤结果的影响。在TNF-/-小鼠中，早在损伤后7天就观察到显著的行为改善。我们表明，TNF-α抑制在体内促进损伤介导的M/Ms从促炎表型向抗炎表型极化。此外，脊髓损伤后M/Ms中积累的铁增加了TNF-α的表达以及M/Ms向促炎表型的转变。而且，补充锌减少了铁过载引起的继发性损伤。总之，我们发现敲除TNF-α通过抑制铁死亡和促进巨噬细胞向抗炎表型转变，促进小鼠脊髓损伤后运动功能的恢复，表明这种治疗方法对脊髓损伤具有巨大潜力。
