Toll-Like Receptor 4-Dependent Microglial Activation Mediates Spinal Cord Ischemia-Reperfusion Injury

作者：Bell Marshall T^*; Puskas Ferenc; Agoston Viktor A; Cleveland Joseph C Jr; Freeman Kirsten A; Gamboni Fabia; Herson Paco S; Meng Xianzhong; Smith Phillip D; Weyant Michael J; Fullerton David A; Reece T Brett

来源：Circulation, 2013, 128(11): S152-S156.

DOI：10.1161/CIRCULATIONAHA.112.000024

• aortic surgery
• aorta
• inflammation
• ischemia
• macrophages
• reperfusion
• spinal cord

Background-Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice.
Methods and Results-TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wildtype microglia had increased TLR-4 expression and production of proinflammatory cytokines.
Conclusions-The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4-mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.

• 出版日期2013-9-10