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 

机构地区：[1]Department of Neurology of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China [2]Nanjing Drum Tower Clinical College of Xuzhou Medical University,Nanjing,Jiangsu Province,China [3]Institute of Brain Sciences,Nanjing University,Nanjing,Jiangsu Province,China [4]Jiangsu Key Laboratory for Molecular Medicine,Medical School of Nanjing University,Nanjing,Jiangsu Province,China [5]Jiangsu Province Stroke Center for Diagnosis and Therapy,Nanjing,Jiangsu Province,China [6]Nanjing Neurology Clinic Medical Center,Nanjing,Jiangsu Province,China [7]Department of Neurology,Lianyungang Municipal Hospital,Affiliated Hospital of Xuzhou Medical University,Lianyungang,Jiangsu Province,China [8]Department of Neurosurgery of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China [9]Department of Neurosurgery,Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University,Xuzhou,Jiangsu Province,China [10]Jiangsu Key Laboratory of Immunity and Metabolism,Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity,Xuzhou Medical University,Xuzhou,Jiangsu Province,China [11]Department of Neurology,Second Affiliated Hospital of Xuzhou Medical University,Xuzhou,Jiangsu Province,China

出　　处：《Neural Regeneration Research》2023年第5期1033-1039,共7页中国神经再生研究（英文版）

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)。

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.

关 键 词：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) 

分 类 号：R743.31[医药卫生—神经病学与精神病学]