摘要We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357-395 of C-X3-C motif chemokine ligand 1(CX3CL1)to induce microglia polarization.More importantly,the peptide Tat-CX3CL1(comprising amino acids 357-395 of CX3CL1)disrupts the interaction between postsynaptic density-93 and CX3CL1,reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke.However,the mechanism underlying these effects remains unclear.In the current study,we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points.The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion,whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion.We found that the peptide Tat-CX3CL1(357-395aa)facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3CL1.Furthermore,the a disintegrin and metalloprotease domain 17(ADAM17)inhibitor GW280264x,which inhibits metalloprotease activity and prevents CX3CL1 from being sheared into its soluble form,facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3CL1 formation.Additionally,Tat-CX3CL1(357-395aa)attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31-34 days following surgery and immunofluorescence staining at 35 days after stroke,respectively.In conclusion,Tat-CX3CL1(357-395aa)facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2.Therefore,the Tat-CX3CL1(357-395aa)is a potential therapeutic agent for ischemic stroke.