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

Libin Ni,Xiaolei Zhang,Liaojun Sun,Zhenxuan Shao,Jian Xiao,Naifeng Tian,Chongan Huang,Xiangyang Wang,Yifei Zhou,Sheng Wang,Aimin Wu,Yaosen Wu,Di Zhang

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.

Highlights

Traumatic spinal cord injury is a critical medical condition with serious consequences and one of the leading causes of disability and death worldwide [1, 2]
The results showed the Sham group, which indicated that the posterior limb that the expression of immunoresponsive gene 1 (Irg-1) mRNA and protein increased in the movement of the spinal cord injury (SCI) mice is severely impaired
Hematoxylin and eosin (H&E) staining to stimulate microglia and establish a time and concentration and Nissl staining were performed to observe the morphology of gradient in vitro

Summary

Introduction

Traumatic spinal cord injury is a critical medical condition with serious consequences and one of the leading causes of disability and death worldwide [1, 2]. Traumatic spinal cord injury causes primary and secondary neurological damage [3]. Primary injury is spinal cord structural injury caused by trauma [4]. The secondary damage is long-lasting, and its pathological process includes oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, etc. The interaction between activated microglia and injured neurons is the basis of the pathological and repair processes of the injured CNS [8]. There are no satisfactory methods and strategies for the treatment of SCI in clinical trials, targeting inflammation caused by activation of microglia has been considered as a potential treatment for spinal cord injury [9]

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