Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits
Sung-Chun Tang *{dagger}, Thiruma V. Arumugam *{ddagger}, Xiangru Xu *, Aiwu Cheng *, Mohamed R. Mughal *, Dong Gyu Jo *{sect}, Justin D. Lathia *, Dominic A. Siler *, Srinivasulu Chigurupati *, Xin Ouyang *, Tim Magnus *¶, Simonetta Camandola *, and Mark P. Mattson *||**
*Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224; {dagger}Stroke Center, Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan; {ddagger}Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, TX 79106; {sect}College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea; and ||Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
Edited by Don W. Cleveland, University of California at San Diego, La Jolla, CA, and approved July 13, 2007 (received for review March 19, 2007)
Published online before print August 10, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0702553104
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.
Author contributions: S.-C.T., T.V.A., and M.P.M. designed research; S.-C.T., T.V.A., X.X., A.C., M.R.M., D.G.J., J.D.L., D.A.S., S.C., X.O., T.M., and S.C. performed research; S.-C.T., T.V.A., D.G.J., J.D.L., D.A.S., and S.C. analyzed data; and T.V.A. and M.P.M. wrote the paper.
The authors declare no conflict of interest.
¶Present address: Department of Neurology, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
**To whom correspondence should be addressed.
Mark P. Mattson, E-mail: mattsonm@grc.nia.nih.gov
www.pnas.org/cgi/doi/10.1073/pnas.0702553104 |
