Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke.
OBJECTIVE
Psychological stress causes an inflammatory response in the brain and is able to exacerbate brain damage caused by experimental stroke. We previously reported that subacute immobilization stress in mice worsens stroke outcome through mechanisms that involve inflammatory mechanisms, such as accumulation of oxidative/nitrosative mediators and expression of inducible nitric oxide synthase and cyclooxygenase-2 in the brain. Some of these inflammatory mediators could be regulated by innate immunity, the activation of which takes place in the brain and produces an inflammatory response mediated by toll-like receptors (TLRs). Recently, we described the implications of TLR4 in ischemic injury, but the role of TLR4 in stress has not yet been examined. We therefore investigated whether inflammation produced by immobilization stress differs in mice that lack a functional TLR4 signaling pathway.


METHODS
We used an experimental paradigm consisting of the exposure of mice to repeated immobilization sessions (1 hour daily for 7 days) before permanent middle cerebral artery occlusion.


RESULTS
We found that TLR4-deficient mice subjected to subacute stress had a better behavioral condition compared with normal mice (C3H/HeN) and that this effect was associated with a minor inflammatory response (cyclooxygenase-2 and inducible nitric oxide synthase expression) and lipid peroxidation (malondialdehyde levels) in brain tissue. Furthermore, previous exposure to stress was followed by a smaller infarct volume after permanent middle cerebral artery occlusion in TLR4-deficient mice than in mice that express TLR4 normally.


CONCLUSIONS
Our results indicate that TLR4 is involved in the inflammatory response after subacute stress and its exacerbating effect on stroke. These data implicate the effects of innate immunity on inflammation and damage in the brain after stroke.
Caso
Javier R
JR
Facultad de Medicina, Universidad Complutense Madrid, Madrid, Spain.
Pradillo
Jesus M
JM
Hurtado
Olivia
O
Leza
Juan C
JC
Moro
Maria A
MA
Lizasoain
Ignacio
I
D000818:Animals; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000150:complications / Q000276:immunology* / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics; D004660:Encephalitis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D015213:Neuroimmunomodulation / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009195:Peroxidase / Q000378:metabolism; D020127:Recovery of Function; D012149:Restraint, Physical; D015398:Signal Transduction / Q000276:immunology; D013315:Stress, Psychological / Q000150:complications / Q000276:immunology*; D020521:Stroke / Q000150:complications / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D003345:Corticosterone