Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits.

Abstract

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.

• Authors: Sung-Chun Tang, Thiruma V Arumugam, Xiangru Xu, Aiwu Cheng, Mohamed R Mughal, Dong Gyu Jo, Justin D Lathia, Dominic A Siler, Srinivasulu Chigurupati, Xin Ouyang, Tim Magnus, Simonetta Camandola, Mark P Mattson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 34 Pg. 13798-803 (Aug 21 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17693552 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Transcription Factor AP-1
• Interferon-gamma
• JNK Mitogen-Activated Protein Kinases
• Caspase 3

Topics

• Animals
• Brain Ischemia (genetics, metabolism, pathology)
• Caspase 3 (metabolism)
• Cell Death
• Disease Models, Animal
• Enzyme Activation
• Interferon-gamma (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism)
• Signal Transduction
• Stroke (genetics, metabolism, pathology)
• Toll-Like Receptor 2 (deficiency, genetics, metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)
• Transcription Factor AP-1 (metabolism)