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The Journal of Neuroscience, December 6, 2006, 26(49):12826-12837; doi:10.1523/JNEUROSCI.4937-05.2006

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Cellular/Molecular
Toll-Like Receptor 2 Signaling in Response to Brain Injury: An Innate Bridge to Neuroinflammation

Alicia A. Babcock,^1,2 Martin Wirenfeldt,¹ Thomas Holm,¹ Helle H. Nielsen,¹ Lasse Dissing-Olesen,¹ Henrik Toft-Hansen,^1,2 Jason M. Millward,² Regine Landmann,³ Serge Rivest,⁴ Bente Finsen,¹ and Trevor Owens^1,2

¹Medical Biotechnology Center, University of Southern Denmark, 5000 Odense C, Denmark, ²Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada H3A 2B4, ³Division of Infectious Diseases, Department of Research, University Hospital, 4031 Basel, Switzerland, and ⁴Laboratory of Molecular Endocrinology, Centre Hospitalier Université Laval Research Center, and Department of Anatomy and Physiology, Laval University, Quebec, Quebec, Canada G1V 4G2

Correspondence should be addressed to Trevor Owens, Medical Biotechnology Center, University of Southern Denmark, Winsloewparken 25, 2 5000 Odense C, Denmark. Email: towens{at}health.sdu.dk

Reactive gliosis is a prominent feature of neurodegenerative and neuroinflammatory disease in the CNS, yet the stimuli that drive this response are not known. There is growing appreciation that signaling through Toll-like receptors (TLRs), which is key to generating innate responses to infection, may have pathogen-independent roles. We show that TLR2 was selectively upregulated by microglia in the denervated zones of the hippocampus in response to stereotactic transection of axons in the entorhinal cortex. In mice lacking TLR2, there were transient, selective reductions in lesion-induced expression of cytokines and chemokines. Recruitment of T cells, but not macrophages, was delayed in TLR2-deficient mice, as well as in mice lacking TNFR1 (tumor necrosis factor receptor 1). TLR2 deficiency also affected microglial proliferative expansion, whereas all of these events were unaffected in TLR4-mutant mice. Consistent with the fact that responses in knock-out mice had all returned to wild-type levels by 8 d, there was no evidence for effects on neuronal plasticity at 20 d. These results identify a role for TLR2 signaling in the early glial response to brain injury, acting as an innate bridge to neuroinflammation.

Key words: hippocampus; neuroinflammation; axotomy; cytokines; chemokines; microglia; leukocytes

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Received July 11, 2005; revised Sept. 14, 2006; accepted Oct. 30, 2006.

Correspondence should be addressed to Trevor Owens, Medical Biotechnology Center, University of Southern Denmark, Winsloewparken 25, 2 5000 Odense C, Denmark. Email: towens{at}health.sdu.dk

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