Cerebral ischemia is a leading cause of death and long-term disability worldwide.Evidence suggests that immune/inflammatory responses are involved in cerebral ischemic injury.Toll-like receptors (TLRs), a family of signaling molecules, play a critical role in the induction of inflammatory responses.TLR signaling pathways are mainly mediated by intracellular adaptors, myeloid differentiation primary-response protein-88 (MyD88), and TIR domain-containing adaptor protein (TRIF).While our and others studies have shown that TLRs are implicated in cerebral ischemic injury, little is known about the role of MyD88 and TRIF in the pathological process following cerebral ischemia.The present study, in a mouse model of cerebral ischemia induced by transient middle cerebral artery occlusion, examined the activation of NF-κB and IRF-3 signaling, neurological function and cerebral infarct size in MyD88 knockout (KO) mice, TRIFKO and wild type (WT) mice.We found that NF-κB but not TRF-3 signaling was activated in ischemic brains.Interestingly, MyD88 deficit but not TRIF deficit inhibited the activation of NFκB signaling induced by cerebral ischemia.Moreover, compared to WT mice, neurological function was improved and infarct size was reduced in MyD88KO but not in TRIFKO mice.Our results demonstrate that the MyD88-dependent but not the TRIF-dependent signaling pathway contributes to the activation of NF-κB signaling and brain injury after acute cerebral ischemia.