title: Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR4- and MyD88-dependent pathway.
abstract: BACKGROUND
  Toll-like receptors (TLR) constitute a highly conserved class of receptors through which the innate immune system responds to both pathogen- and host-derived factors. Although TLRs are involved in a wide range of central nervous system (CNS) disorders including neurodegenerative diseases, the molecular events leading from CNS injury to activation of these innate immune receptors remain elusive. The stress protein heat shock protein 60 (HSP60) released from injured cells is considered an endogenous danger signal of the immune system. In this context, the main objective of the present study was to investigate the impact of extracellular HSP60 on the brain in vivo.
  
  
  RESULTS
  We show here that HSP60 injected intrathecally causes neuronal and oligodendrocyte injury in the CNS in vivo through TLR4-dependent signaling. Intrathecal HSP60 results in neuronal cell death, axonal injury, loss of oligodendrocytes, and demyelination in the cerebral cortex of wild-type mice. In contrast both mice lacking TLR4 and the TLR adaptor molecule MyD88 are protected against deleterious effects induced by HSP60. In contrast to the exogenous TLR4 ligand, lipopolysaccharide, intrathecal HSP60 does not induce such a considerable inflammatory response in the brain. In the CNS, endogenous HSP60 is predominantly expressed in neurons and released during brain injury, since the cerebrospinal fluid (CSF) from animals of a mouse stroke model contains elevated levels of this stress protein compared to the CSF of sham-operated mice.
  
  
  CONCLUSIONS
  Our data show a direct toxic effect of HSP60 towards neurons and oligodendrocytes in the CNS. The fact that these harmful effects involve TLR4 and MyD88 confirms a molecular pathway mediated by the release of endogenous TLR ligands from injured CNS cells common to many forms of brain diseases that bi-directionally links CNS injury and activation of the innate immune system to neurodegeneration and demyelination in vivo.
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. rosenbergerkaren@aol.com.
authors.forename: Karen
authors.initials: K
authors.lastname: Rosenberger
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. paul.dembny@charite.de.
authors.forename: Paul
authors.initials: P
authors.lastname: Dembny
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. katja.derkow@charite.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Derkow
authors.affiliation: Center for Stroke Research, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. odilo.engel@charite.de.
authors.forename: Odilo
authors.initials: O
authors.lastname: Engel
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. christina.krueger@charite.de.
authors.forename: Christina
authors.initials: C
authors.lastname: Krüger
authors.affiliation: Cellular Neurosciences, Max Delbrueck Center for Molecular Medicine, Robert Roessle Str. 10, 13125, Berlin, Germany. Susanne.Wolf@mdc-berlin.de.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.affiliation: Cellular Neurosciences, Max Delbrueck Center for Molecular Medicine, Robert Roessle Str. 10, 13125, Berlin, Germany. kettenmann@mdc-berlin.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.affiliation: Department of Hepatology and Gastroenterology, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. eckart.schott@charite.de.
authors.forename: Eckart
authors.initials: E
authors.lastname: Schott
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. andreas.meisel@charite.de.|Center for Stroke Research, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. andreas.meisel@charite.de.|Cluster of Excellence NeuroCure, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. andreas.meisel@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.affiliation: Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. seija.lehnardt@charite.de.|Cluster of Excellence NeuroCure, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. seija.lehnardt@charite.de.|Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. seija.lehnardt@charite.de.
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D018834:Chaperonin 60 / Q000378:metabolism* / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D018834:Chaperonin 60; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4