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

Abstract

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, wild-type 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.

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

“…It was also found that TLR4‐dependent microglial activation mediates spinal cord ischemia–reperfusion injury 11. TLR3 and TLR4 share a common signaling pathway via TRIF17; therefore, we sought to elucidate whether TLR4 was also stimulated by shock waves.…”

“…Besides acute paraplegia directly after surgery, delayed‐onset paraplegia has been observed 10. Toll‐like receptor (TLR) 4–dependent microglial activation has been identified in this setting to mediate spinal cord ischemia–reperfusion injury 11. Microglia are spinal resident macrophages and the main cell type in the resting central nervous system that expresses TLR3 and TLR4 12, 13.…”

Photothrombosis-induced Focal Ischemia as a Model of Spinal Cord Injury in Mice

“…Few of the shortcomings include lack of an anatomically clear ischemic penumbra, which is the target of many neuroprotective drugs, and the absence of reperfusion. It is well known that reperfusion following ischemia is characterized by changes like increased production of reactive oxygen species, infiltration of inflammatory cells and increased cytokine production [30][31][32] . Lack of reperfusion in PT means the changes associated with reperfusion injury in SC will remain difficult to study using this model.…”

Ischemia-reperfusion injury: evidences for translational research

“…The neural tissue is very susceptible to oxidative damage, due to its high oxygen requirement (up to 20% of the total oxygen intake, even though it is 2% of the total body weight) and its low antioxidant activity with respect to other tissues (8). Nevertheless, IRI in the spinal cord is also caused by microglial activation as well as blood spinal cord barrier disruption (9,10). Thus, a promising therapeutic approach to CSM has to target multiple mechanisms of injury.…”