Toll-like receptor 9: a new target of ischemic preconditioning in the brain.
Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)alpha-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFalpha levels before MCAO and that TNFalpha is required for subsequent reduction in damage, as mice lacking TNFalpha are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.
Stevens
Susan L
SL
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Ciesielski
Thomas M P
TM
Marsh
Brenda J
BJ
Yang
Tao
T
Homen
Delfina S
DS
Boule
Jo-Lynn
JL
Lessov
Nikola S
NS
Simon
Roger P
RP
Stenzel-Poore
Mary P
MP
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019194:Ischemic Preconditioning / Q000379:methods*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C408982:CPG-oligonucleotide; D008024:Ligands; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha