title: 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.
  
  
  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.
authors.affiliation: Departments of Cardiothoracic Surgery (M.T.B., V.A.A., J.C.C., K.A.F., F.G., X.M., P.D.S., M.J.W., D.A.F., T.B.R.) and Anesthesiology (F.P., P.S.H.), University of Colorado, Denver, CO.
authors.forename: Marshall T
authors.initials: MT
authors.lastname: Bell
authors.forename: Ferenc
authors.initials: F
authors.lastname: Puskas
authors.forename: Viktor A
authors.initials: VA
authors.lastname: Agoston
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Freeman
authors.forename: Fabia
authors.initials: F
authors.lastname: Gamboni
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D020760:Spinal Cord Ischemia / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: aorta; aortic surgery; inflammation; ischemia; macrophages; reperfusion; spinal cord