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