Hypoxia-Inducible Factor-1α-Induced Astrocytic D-Dopachrome Tautomerase Activates Microglial Inflammatory Response following Spinal Cord Injury

Abstract

Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurologic dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor, 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 tumor necrosis factor-α, IL-1β, and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using an in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/mitogen-activated protein kinase signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of hypoxia-inducible factor-1α. Hypoxia or dimethyloxallyl glycine stimulation of astrocytes was shown efficient in promoting the expression of hypoxia-inducible factor-1α and D-DT, whereas incubation of the microglia with the astrocytes' conditional medium increased the production of tumor necrosis factor-α, IL-1β, and IL-6. Pharmacologic treatment of the subjects with 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathologic function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.