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TLR2 Mediates Neuroinflammation and Neuronal Damage¹

Olaf Hoffmann^2,*, Johann S. Braun^2,*, Doreen Becker^*, Annett Halle^*, Dorette Freyer^*, Emilie Dagand^*, Seija Lehnardt and Joerg R. Weber^3,*,

^* Department of Neurology and Department of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany

Innate immunity relies on pattern recognition receptors to detect the presence of infectious pathogens. In the case of Gram-positive bacteria, binding of bacterial lipopeptides to TLR2 is currently regarded as an important mechanism. In the present study, we used the synthetic bacterial lipopeptide Pam₃CysSK₄, a selective TLR2 agonist, to induce meningeal inflammation in rodents. In a 6-h rat model, intrathecal application of Pam₃CysSK₄ caused influx of leukocytes into the cerebrospinal fluid (CSF) and induced a marked increase of regional cerebral blood flow and intracranial pressure. In wild-type mice, we observed CSF pleocytosis and an increased number of apoptotic neurons in the dentate gyrus 24 h after intrathecal challenge. Inflammation and associated neuronal loss were absent in TLR2 knockout mice. In purified neurons, cytotoxicity of Pam₃CysSK₄ itself was not observed. Exposure of microglia to Pam₃CysSK₄ induced neurotoxic properties in the supernatant of wild-type, but not TLR2-deficient microglia. We conclude that TLR2-mediated signaling is sufficient to induce the host-dependent key features of acute bacterial meningitis. Therefore, synthetic lipopeptides are a highly specific tool to study mechanisms of TLR2-driven neurodegeneration in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant SFB 507 B6 from the Deutsche Forschungsgemeinschaft (to O.H., J.S.B., and J.R.W.) and a Rahel Hirsch grant from the Charité-Universitätsmedizin Berlin (to S.L.).

² O.H. and J.S.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Joerg R. Weber, Department of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail address: joerg.weber{at}charite.de

⁴ Abbreviations used in this paper: PG, peptidoglycan; ICP, intracranial pressure; CSF, cerebrospinal fluid; LDF, laser Doppler flow; LDH, lactate dehydrogenase.

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