Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (8): 1802-1808.doi: 10.4103/1673-5374.363184

Previous Articles     Next Articles

Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury

Han Zhang1, #, Yu-Ming Hu2, #, Ying-Jie Wang3, Yue Zhou2, Zhen-Jie Zhu2, Min-Hao Chen1, Yong-Jun Wang3, Hua Xu1, *, #br# You-Hua Wang1, *#br#   

  1. 1Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu Province, China; 2Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China; 3Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
  • Online:2023-08-15 Published:2023-02-24
  • Contact: You-Hua Wang, MD, wangyouhua99@163.com; Hua Xu, MD, xuhua1981111@126.com.
  • Supported by:
    This study was supported by the China Postdoctoral Science Foundation, No. 2020M681689 (to YMH), and the Basic Scientific Research Projects of Nantong, Nos. JC2020015 (to HX) and JC2020041 (to YMH).

PDF

51

Abstract: Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation. Overproduced chemokines are responsible for the migratory process of the leukocytes, but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated. We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury. The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes. Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells, and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect. Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor. Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats. Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.

Key words: astrocytes, CD74, chemokine, chemokine C-C motif chemokine ligand 2 (CCL2), cytokine, inflammation, leukocyte, MAPKs, migration inhibitory factor, spinal cord injury