MyD88 Is An Endogenous Protective Factor Against Cerebral Ischemic Injury

Hypoxia-induced depolarization,Mmassive glutamate release,and calcium overload-induced central excitotoxicity are pivotal early events leading to brain ischemic injury.Therefore,elucidating the mechanisms underlying glutamate excitotoxicityearly cerebral ischemic injury during brain ischemia is of particular importance to the research field.Neurons in different areas of the mammalian central nervous system（CNS）exhibit differential tolerance to cerebral hypoperfusionglutamate excitotoxicity,suggesting there are brain area-specific pro-death and pro-survival signals.Toll-like receptors（TLRs）are a group of pattern recognition receptors that play a critical role in the innate immune system.Myeloid differentiation primary response protein 88（MyD88）is one of the key molecules recruited by TLRs.Existing evidence shows that TLR/MyD88-mediated inflammatory processes within the brain might contribute to the middle and late stages of brain ischemic injury.However,knocking out MyD88aggravates brain ischemic injury.Our prior work has shown that MyD88 is differentially expressed in the brain.The expression level of MyD88 correlates well to its protection against cerebral ischemia-induced neurodegeration,suggesting MyD88 is an endogenous pro-survival molecule in the brain.In the study,we have shown that MyD88 plays a protective role in brain ischemia/reperfusion injury.Remarkably,MyD88 reduces the Ca²⁺permeability of AMPA receptor by stabilizing ischemic insult-induced dephoshorylation of Ca²⁺/calmodulin-dependent protein kinase Ⅱ（Ca MKⅡ）in cortical neurons.Further study revealed that phosphorylation of Ca MKⅡ-T286 is the key target of MyD88 participating in the protecting against excitotoxicitybrain ischemia.Additionally,the protective effect of MyD88 in the early stage of ischemia/reperfusion is mediated by Protein phosphatase 2B（PP2B）and PP1.In conclusion,independent on the canonical inflammatory pathway,MyD88 protects neurons against early brain ischemic injury through PP2B/PP1-Ca MKⅡ-Glu A1signaling pathway,which provides a new target for cerebral ischemia treatment.