Zhang Han, Hu Yu-Ming, Wang Ying-Jie, Zhou Yue, Zhu Zhen-Jie, Chen Min-Hao, Wang Yong-Jun, Xu Hua, Wang You-Hua
Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu Province, China.
Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.
Neural Regen Res. 2023 Aug;18(8):1802-1808. doi: 10.4103/1673-5374.363184.
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.
脊髓损伤会导致大量白细胞在损伤部位积聚，这些白细胞会引发过度炎症反应。趋化因子产生过多是白细胞迁移过程的原因，但脊髓驻留细胞产生趋化因子的调控机制尚未完全阐明。我们在脊髓损伤后的不同时间点，检测了脊髓挫伤模型中巨噬细胞迁移抑制因子和趋化因子C-C基序趋化因子配体2的蛋白水平。损伤部位巨噬细胞迁移抑制因子的升高与星形胶质细胞中趋化因子C-C基序趋化因子配体2丰度的增加相一致。用不同浓度的巨噬细胞迁移抑制因子重组蛋白刺激原代培养的星形胶质细胞，可诱导细胞产生趋化因子C-C基序趋化因子配体2，而巨噬细胞迁移抑制因子抑制剂4-碘-6-苯基嘧啶减弱了这种刺激作用。进一步研究巨噬细胞迁移抑制因子介导星形胶质细胞产生趋化因子C-C基序趋化因子配体2的潜在机制发现，巨噬细胞迁移抑制因子通过与CD74受体结合激活细胞内JNK信号通路。脊髓损伤后给予巨噬细胞迁移抑制因子抑制剂4-碘-6-苯基嘧啶，可减少损伤部位趋化因子C-C基序趋化因子配体2招募的小胶质细胞/巨噬细胞，并显著改善大鼠后肢运动功能。我们的研究结果为星形胶质细胞激活的趋化因子在白细胞募集中的作用提供了见解，可能有助于开发针对趋化因子C-C基序趋化因子配体2的干预措施，用于治疗脊髓损伤后的神经炎症。
