Preconditioning reprograms TLR signaling following cerebral ischemia the emergence of a neuroprotective program

LPS preconditioning, achieved by administering a small dose of lipopolysaccharide before stroke, produces strong neuroprotection, likely through Toll like receptor 4 (TLR4) signaling and TNFα induction. Because stroke triggers endogenous TLR activation, with some TLRs worsening injury and others promoting protection, this study tested whether additional TLR ligands can shift post ischemic signaling toward neuroprotection. Systemic preconditioning with CpG oligodeoxynucleotides, a TLR9 ligand, significantly reduced ischemic damage in vivo and protected neurons in vitro. CpG treatment elevated serum TNFα and required TNFα for its effects. These findings show that multiple TLR ligands can induce TNFα dependent neuroprotection against stroke.