Knockout of TNF-α in microglia decreases ferroptosis and convert microglia phenotype after spinal cord injury

Background: 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-alpha(TNF-alpha) ablation protected after SCI by suppressing neuroinflammation and ferroptosis. Though using TNF-alpha knock out mice (TNF-/-), we induced downregulation of TNF-alpha 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-alpha inhibition promote injury-mediated M/Ms polarization from proinflammatory to anti-inflammatory phenotype in vivo. Furthermore, accumulated iron in M/Ms after SCI increased the expression of TNF-alpha 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-alpha 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.