HIF-1α-induced astrocytic D-dopachrome tautomerase activates microglial inflammatory response following spinal cord injury

• Published in: The American journal of pathology
• Main Authors: Li, Aicheng, Li, Mengdi, Xu, Si, Niu, Li, Li, Shaolan, Zhou, Yue, Cao, Zhilong, Cai, Rixin, He, Bingqiang, Guo, Aisong, Li, Aihong, Song, Honghua, Wang, Yongjun, Wang, Yingjie
• Format: Journal Article
• Language: English
• Published: 18.06.2025
• ISSN: 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2025.05.015

Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurological dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor (MIF), is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D-DT, p65NF-κB and the downstream proinflammatory cytokines TNF-α, IL-1β and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-CPPC was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/MAPKs signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of HIF-1α. Hypoxia or DMOG stimulation of astrocytes was shown efficient in promoting the expression of HIF-1α and D-DT, while incubation of the microglia with the astrocytes conditional medium (ACM) was able to increase the production of TNF-α, IL-1β and IL-6. Pharmacological treatment of the subjects with 4-CPPC or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathological function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurological dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor (MIF), is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D-DT, p65NF-κB and the downstream proinflammatory cytokines TNF-α, IL-1β and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-CPPC was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/MAPKs signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of HIF-1α. Hypoxia or DMOG stimulation of astrocytes was shown efficient in promoting the expression of HIF-1α and D-DT, while incubation of the microglia with the astrocytes conditional medium (ACM) was able to increase the production of TNF-α, IL-1β and IL-6. Pharmacological treatment of the subjects with 4-CPPC or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathological function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.