Details

Autor(en) / Beteiligte

• Zhang, Qingxiu
• He, Lei
• Chen, Mo
• Yang, Hui
• Cao, Xiaowei
• Liu, Xiaomei
• Hao, Qi
• Chen, Zhengwei
• Liu, Tengfei
• Wei, Xiu‐e
• Rong, Liangqun

Titel

PSD‐93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1

Ist Teil von

• Journal of neurochemistry, 2021-06, Vol.157 (6), p.2145-2157

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2021

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Post‐synaptic density 93 (PSD‐93) mediates glutamate excitotoxicity induced by ischemic brain injury, which then induces microglial inflammatory response. However, the underlying mechanisms of how PSD‐93 mediates the crosstalk between neurons and microglia in the post‐synaptic dense region remain elusive. CX3 chemokine ligand 1 (CX3CL1) is a chemokine specifically expressed in neurons while its receptor CX3CR1 is highly expressed in microglia. In this study, we examined the interaction of PSD‐93 and CX3CL1 in the crosstalk between neurons and microglia in acute ischemic stroke. We utilized male C57BL/6 mice to establish the middle cerebral artery occlusion model (MCAO) and designed a fusion small peptide Tat‐CX3CL1 (357‐395aa) to inhibit PSD‐93 and CX3CL1 interaction. The combination peaks of PSD‐93 and CX3CL1 at 6 hr after I/R were observed. The binding sites were located at the 420–535 amino acid sequence of PSD‐93 and 357–395 amino acid sequence of CX3CL1. Tat‐CX3CL1 (357‐395aa) could inhibit the interaction of PSD‐93 and CX3CL1 and inhibited the pro‐inflammatory cytokine IL‐1β and TNF‐α expression and provided neuroprotection following reperfusion. Together, these data suggest that PSD‐93 binds CX3CL1 to activate microglia and initiate neuroinflammation. Specific blockade of PSD‐93‐CX3CL1 interaction reduces I/R induced neuronal cell death, and provides a new therapeutic target for ischemic stroke. We proposed that PSD‐93 facilitates the splintering of CX3CL1 into a soluble form through binding CX3CL1, which enables it to be recruited into the microglia cell surface, bind to CX3CR1 and activates microglia cells and initiates the occurrence of inflammatory response. And we further confirmed the binding sites were located at the 420‐535 amino acid sequence of PSD‐93 and 357‐395 amino acid sequence of CX3CL1. These findings revealed the underlying mechanism of PSD‐93 mediate neuron‐microglia dialogue during cerebral ischemia and provided a new therapeutic target for ischemic stroke.