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TLR2 and Caspase-8 Are Essential for Group B Streptococcus-Induced Apoptosis in Microglia¹

Seija Lehnardt^2,*, Julia Wennekamp, Dorette Freyer, Christian Liedtke, Christina Krueger^*, Robert Nitsch^*, Ingo Bechmann^¶, Joerg R. Weber^*, and Philipp Henneke

^* Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; Center for Pediatrics and Adolescent Medicine, Albert-Ludwigs-University, Freiburg, Germany; Department of Neurology, Charité-Universitaetsmedizin Berlin, Berlin, Germany; Department of Medicine III, University Hospital Aachen, Aachen University, Aachen, Germany; and ^¶ Institute of Clinical Neuroanatomy, J.W. Goethe-University, Frankfurt/Main, Germany

Microglia, the resident innate immune cells of the CNS, detect invading pathogens via various receptors, including the TLR. Microglia are involved in a number of neurodegenerative diseases in which their activation may be detrimental to neurons. It is largely unknown how this potentially deleterious action can be countered on a cellular level. We previously found that the interaction of TLR2 with group B Streptococcus (GBS), the most important pathogen in neonatal bacterial meningitis, activates microglia that in turn generate neurotoxic NO. We report in this study that GBS not only activates microglia, but also induces apoptosis in these cells via TLR2 and the TLR-adaptor molecule MyD88. Soluble toxic mediators, such as NO, are not responsible for this form of cell death. Instead, interaction of GBS with TLR2 results in formation and activation of caspase-8, a process that involves the transcription factor family Ets. Whereas caspase-8 plays an essential role in GBS-induced microglial apoptosis, caspase-3 is dispensable in this context. We suggest that TLR2- and caspase-8-mediated microglial apoptosis constitutes an autoregulatory mechanism that limits GBS-induced overactivation of the innate immune system in the CNS.

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 in part by a Rahel-Hirsch Grant from Charité-Universitaetsmedizin Berlin (to S.L.), by the National Institutes of Health, and by Deutsche Forschungsgemeinschaft (to P.H.).

² Address correspondence and reprint requests to Dr. Seija Lehnardt, Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail address: seija.lehnardt{at}charite.de

³ Abbreviations used in this paper: GBS, group B Streptococcus; AICD, activation-induced cell death; DAPI, 4',6-diamidino-2-phenylindole; FasL, Fas ligand; HF, heat fixed; IB4, isolectin B4; LTA, lipoteichoic acid.