Fractalkine/CX3CR1 axis is critical for neuroprotection induced by hypoxic postconditioning against cerebral ischemic injury

• Published in: Cell communication and signaling 2024-09, Vol.22 (1), p.457-18, Article 457
• Main Authors: Zhan, Lixuan, Qiu, Meiqian, Zheng, Jianhua, Lai, Meijing, Lin, Kunqin, Dai, Jiahua, Sun, Weiwen, Xu, En
• Format: Article
• Language: English
• Subjects: Akt; Animals; Brain damage; Brain Ischemia - genetics; Brain Ischemia - metabolism; Brain Ischemia - pathology; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - pathology; Causes of; Cerebral ischemia; Chemokine CX3CL1 - genetics; Chemokine CX3CL1 - metabolism; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - metabolism; CX3CR1; Fractalkine; Hypoxic postconditioning; Ischemia; Ischemic Postconditioning; Male; Microglia - metabolism; Microglia - pathology; Neuroinflammation; Neurons; Neurons - metabolism; Neurons - pathology; Neuroprotection; Prevention; Rats; Rats, Sprague-Dawley; Risk factors; Signal Transduction
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-024-01830-4

Microglial activation-mediated neuroinflammation is a major contributor to neuronal damage after cerebral ischemia. The Fractalkine (FKN)/CX3C chemokine receptor 1 (CX3CR1) axis plays a critical role in regulating microglial activation and neuroinflammation. The aim of this study is to ascertain the role and mechanism of FKN/CX3CR1 axis in hypoxic postconditioning (HPC)-induced anti-inflammatory and neuroprotective effects on transient global cerebral ischemia (tGCI). We found that HPC suppressed microglial activation and alleviated neuroinflammation in hippocampal CA1 after tGCI. Meanwhile, HPC upregulated the expression of FKN and CX3CR1 in neurons, but it downregulated the expression of CX3CR1 in glial cells after tGCI. In addition, the overexpression of FKN induced by the administration of FKN-carried lentivirus reduced microglial activation and inhibited neuroinflammation in CA1 after tGCI. Furthermore, silencing CX3CR1 with CX3CRi-carried lentivirus in CA1 after tGCI suppressed microglial activation and neuroinflammation and exerted neuroprotective effects. Finally, the overexpression of FKN caused a marked increase of neuronal CX3CR1 receptors, upregulated the phosphorylation of Akt, and reduced neuronal loss of rats in CA1 after tGCI. These findings demonstrated that HPC protected against neuronal damage in CA1 of tGCI rats through inhibiting microglial activation and activating Akt signaling pathway via FKN/CX3CR1 axis.