Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits.
The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.
Tang
Sung-Chun
SC
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Arumugam
Thiruma V
TV
Xu
Xiangru
X
Cheng
Aiwu
A
Mughal
Mohamed R
MR
Jo
Dong Gyu
DG
Lathia
Justin D
JD
Siler
Dominic A
DA
Chigurupati
Srinivasulu
S
Ouyang
Xin
X
Magnus
Tim
T
Camandola
Simonetta
S
Mattson
Mark P
MP
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3
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