Knockout of TNF-α in microglia decreases ferroptosis and convert microglia phenotype after spinal cord injury
Fanzhuo Zeng,
Anqi Chen,
Wei Chen,
Shuai Cheng,
Sen Lin,
Rongcheng Mei,
Xifan Mei
Affiliations
Fanzhuo Zeng
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; Department of Neurobiology, School of Basic Medical Sciences, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, 510515, Guangdong, China
Anqi Chen
Department of Orthopedics, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, Hubei, China; Medical College of Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China
Wei Chen
Department of Orthopedics, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, Hubei, China
Shuai Cheng
Department of Orthopedics, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121002, Liaoning, China
Sen Lin
Department of Orthopedics, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121002, Liaoning, China; Corresponding author. Jinzhou Medical University, Jinzhou, Liaoning Province, China.
Rongcheng Mei
Department of Orthopedics, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, Hubei, China; Medical College of Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China; Corresponding author. Xiangyang central hospital, Affiliated hospital of Hubei University of Arts and Science, Hubei Province, China.
Xifan Mei
Department of Orthopedics, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121002, Liaoning, China; Corresponding author. Professor. Jinzhou Medical University, Jinzhou, Liaoning Province, China.
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-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.
