Blocking postsynaptic density-93 binding to C-X3-C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke

作     者：Xiao-Wei Cao Hui Yang Xiao-Mei Liu Shi-Ying Lou Li-Ping Kong Liang-Qun Rong Jun-Jun Shan Yun Xu Qing-Xiu Zhang Xiao-Wei Cao;Hui Yang;Xiao-Mei Liu;Shi-Ying Lou;Li-Ping Kong;Liang-Qun Rong;Jun-Jun Shan;Yun Xu;Qing-Xiu Zhang

作者机构：Department of Neurology of Drum Tower HospitalMedical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjingJiangsu ProvinceChina Nanjing Drum Tower Clinical College of Xuzhou Medical UniversityNanjingJiangsu ProvinceChina Institute of Brain SciencesNanjing UniversityNanjingJiangsu ProvinceChina Jiangsu Key Laboratory for Molecular MedicineMedical School of Nanjing UniversityNanjingJiangsu ProvinceChina Jiangsu Province Stroke Center for Diagnosis and TherapyNanjingJiangsu ProvinceChina Nanjing Neurology Clinic Medical CenterNanjingJiangsu ProvinceChina Department of NeurologyLianyungang Municipal HospitalAffiliated Hospital of Xuzhou Medical UniversityLianyungangJiangsu ProvinceChina Department of Neurosurgery of Drum Tower HospitalMedical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjingJiangsu ProvinceChina Department of NeurosurgeryAffiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhouJiangsu ProvinceChina Jiangsu Key Laboratory of Immunity and MetabolismDepartment of Pathogen Biology and Immunology and Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhouJiangsu ProvinceChina Department of NeurologySecond Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu ProvinceChina 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2023年第18卷第5期

页      面：1033-1039页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China,Nos. 82071304 (to QXZ), 81671149 (to QXZ),and 81971179 (to XML) the Natural Science Foundation of Jiangsu Province,Nos. BK20191463 (to XML) and BK20161167 (to QXZ) 

主　　题：a disintegrin and metalloprotease domain 17 cerebral ischemia/reperfusion C-X3-C motif chemokine ligand 1 GW280264x microglia neuroinflammation postsynaptic density-93 Tat-CX3CL1(357–395aa) 

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(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, 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-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) 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-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.