Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.
Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.
Lehnardt
Seija
S
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Massillon
Leon
L
Follett
Pamela
P
Jensen
Frances E
FE
Ratan
Rajiv
R
Rosenberg
Paul A
PA
Volpe
Joseph J
JJ
Vartanian
Timothy
T
D000818:Animals; D017209:Apoptosis; D024201:Bystander Effect / Q000276:immunology*; D002540:Cerebral Cortex / Q000166:cytology / Q000276:immunology*; D002642:Chick Embryo; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000166:cytology / Q000276:immunology*; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009410:Nerve Degeneration / Q000276:immunology*; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology*
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides