Knockout of TNF-α in Microglia Decreases Ferroptosis and Convert Microglia Phenotype After Spinal Cord Injury

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Sep 16

PMID 39281475

Authors

Fanzhuo Zeng

Anqi Chen

Wei Chen

Shuai Cheng

Sen Lin

Rongcheng Mei

Xifan Mei

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury.

Yang S, Yu B, Zhang Q, Zhang Y, Fu L, Zhou B J Transl Med. 2025; 23(1):60.

PMID: 39806436 PMC: 11726942. DOI: 10.1186/s12967-024-05916-y.

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