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

• Published in: Cell death & disease 2022-02, Vol.13 (2), p.140-140, Article 140
• Main Authors: Ni, Libin, Xiao, Jian, Zhang, Di, Shao, Zhenxuan, Huang, Chongan, Wang, Sheng, Wu, Yaosen, Tian, Naifeng, Sun, Liaojun, Wu, Aimin, Zhou, Yifei, Wang, Xiangyang, Zhang, Xiaolei
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/21; 13/51; 38/77; 42/89; 631/378/1934; 631/378/2596/1953; 631/80/82/23; 64/60; 692/699/578; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Hydro-Lyases - genetics; Hydro-Lyases - metabolism; Immunology; Inflammation; Inflammation - metabolism; Life Sciences; Lipopolysaccharides; Mice; Microglia; Microglia - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Spinal Cord - metabolism; Spinal cord injuries; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - genetics; Succinates
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04592-4

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.