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The Journal of Neuroscience, March 5, 2008, 28(10):2320-2331; doi:10.1523/JNEUROSCI.4760-07.2008

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Cellular/Molecular
A Vicious Cycle Involving Release of Heat Shock Protein 60 from Injured Cells and Activation of Toll-Like Receptor 4 Mediates Neurodegeneration in the CNS

Seija Lehnardt,^1,2 Eckart Schott,³ Thorsten Trimbuch,¹ Dinah Laubisch,¹ Christina Krueger,¹ Gregory Wulczyn,¹ Robert Nitsch,¹ and Joerg R. Weber¹

¹Center for Anatomy, Institute for Cell Biology and Neurobiology, and ²Cecilie-Vogt-Clinic for Neurology, Charité-Universitaetsmedizin Berlin, 10117 Berlin, Germany, and ³Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany

Correspondence should be addressed to Seija Lehnardt, Center for Anatomy, Institute for Cell Biology and Neurobiology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Email: seija.lehnardt{at}charite.de

Infection, ischemia, trauma, and neoplasia elicit a similar inflammatory response in the CNS characterized by activation of microglia, the resident CNS monocyte. The molecular events leading from CNS injury to the activation of innate immunity is not well understood. We show here that the intracellular chaperone heat shock protein 60 (HSP60) serves as a signal of CNS injury by activating microglia through a toll-like receptor 4 (TLR4)-dependent and myeloid differentiation factor 88 (MyD88)-dependent pathway. HSP60 is released from CNS cells undergoing necrotic or apoptotic cell death and specifically binds to microglia. HSP60-induced synthesis of neurotoxic nitric oxide by microglia is dependent on TLR4. HSP60 induces extensive axonal loss and neuronal death in CNS cultures from wild-type but not TLR4 or MyD88 loss-of-function mutant mice. This is the first evidence of an endogenous molecular pathway common to many forms of neuronal injury that bidirectionally links CNS inflammation with neurodegeneration.

Key words: innate immunity; toll-like receptor; neurodegeneration; inflammation; heat shock protein; microglia

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Received Feb. 13, 2007; revised Dec. 2, 2007; accepted Dec. 2, 2007.

Correspondence should be addressed to Seija Lehnardt, Center for Anatomy, Institute for Cell Biology and Neurobiology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Email: seija.lehnardt{at}charite.de

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