1. ¹Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA
2. ²Robert S. Dow Neurobiology Laboratories, Legacy Clinical Research and Technology Center, Portland, Oregon, USA

Correspondence: Dr MP Stenzel-Poore, Department of Molecular Microbiology and Immunology, L220, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. E-mail: poorem@ohsu.edu

Received 25 July 2007; Revised 3 December 2007; Accepted 4 December 2007; Published online 9 January 2008.

Abstract

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