Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice

  • Cell Death Dis. 2022 Feb 10;13(2):140. doi: 10.1038/s41419-022-04592-4.
Libin Ni   #  1  2  3 ,  Jian Xiao   #  1  2  3 ,  Di Zhang   #  1  2  3 ,  Zhenxuan Shao  4 ,  Chongan Huang  1  2  3 ,  Sheng Wang  1  2  3 ,  Yaosen Wu  1  2  3 ,  Naifeng Tian  1  2  3 ,  Liaojun Sun  1  2  3 ,  Aimin Wu  1  2  3 ,  Yifei Zhou  5  6  7 ,  Xiangyang Wang  8  9  10 ,  Xiaolei Zhang  11  12  13  14
Affiliations
  • 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 2. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China.
  • 3. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 4. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 5. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 6. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China. [email protected].
  • 7. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 8. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 9. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China. [email protected].
  • 10. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 11. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 12. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China. [email protected].
  • 13. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. [email protected].
  • 14. Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 35145070 DOI: 10.1038/s41419-022-04592-4
Abstract

The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. Secondary injury is a major target for SCI therapy, whereas microglia play an important role in secondary injury. The immunoresponsive gene 1 (Irg-1) has been recorded as one of the most significantly upregulated genes in SCI tissues in gene chip data; however, its role in SCI remains unclear. This study aims to illustrate the role of Irg-1 as well as its regulated metabolite itaconate in SCI. It was demonstrated that the expression of Irg-1 was increased in spinal cord tissues in mice as well as in microglia stimulated by lipopolysaccharides (LPS). It was also shown that overexpression of Irg-1 may suppress LPS-induced inflammation in microglia, while these protective effects were attenuated by Nrf2 silencing. In vivo, overexpression of Irg-1 was shown to suppress neuroinflammation and improve motor function recovery. Furthermore, treatment of microglia with itaconate demonstrated similar inflammation suppressive effects as Irg-1 overexpression in vitro and improved motor function recovery in vivo. In conclusion, the current study shows that Irg-1 and itaconate are involved in the recovery process of SCI, either Irg-1 overexpression or itaconate treatment may provide a promising strategy for the treatment of SCI.

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