Toll-like receptor 9: A new target of ischemic preconditioning in the brain

Susan L. Stevens, Thomas M.P. Ciesielski, Brenda J. Marsh, Tao Yang, Delfina S. Homen, Jo Lynn Boule, Nikola S. Lessov, Roger P. Simon, Mary P. Stenzel-Poore

Research output: Contribution to journalArticlepeer-review

141 Scopus citations


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)α-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 TNFα levels before MCAO and that TNFα is required for subsequent reduction in damage, as mice lacking TNFα 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.

Original languageEnglish (US)
Pages (from-to)1040-1047
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number5
StatePublished - May 2008
Externally publishedYes


  • CpG
  • Ischemic tolerance
  • Neuroprotection
  • Preconditioning
  • TLR9

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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