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Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury.
- Source :
-
Circulation [Circulation] 2013 Sep 10; Vol. 128 (11 Suppl 1), pp. S152-6. - Publication Year :
- 2013
-
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.<br />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.<br />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.
- Subjects :
- Animals
Cell Survival physiology
Cells, Cultured
Inflammation Mediators metabolism
Male
Mice
Mice, Inbred C3H
Mice, Knockout
Reperfusion Injury pathology
Spinal Cord Ischemia pathology
Toll-Like Receptor 4 deficiency
Microglia metabolism
Reperfusion Injury metabolism
Spinal Cord Ischemia metabolism
Toll-Like Receptor 4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 128
- Issue :
- 11 Suppl 1
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 24030400
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.112.000024