Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, PR China.
Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Henan, 450000, PR China.
Redox Biol. 2023 Dec;68:102960. doi: 10.1016/j.redox.2023.102960. Epub 2023 Nov 10.
C-X-C chemokine receptor type 4 (CXCR4) is critical for homeostasis of the adaptive and innate immune system in some CNS diseases. Bruton's tyrosine kinase (BTK) is an essential kinase that regulates inflammation in immune cells through multiple signaling pathways. This study aims to explore the effect of CXCR4 and BTK on neuroinflammation in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Our results showed that the expression of CXCR4 and p-BTK increased significantly at 24 h after SAH in vivo and in vitro. Ibrutinib improved neurological impairment, BBB disruption, cerebral edema, lipid peroxidation, neuroinflammation and neuronal death at 24 h after SAH. Inhibition of BTK phosphorylation promoted the in vitro transition of hemin-treated proinflammatory microglia to the anti-inflammatory state, inhibited the p-P65 expression and microglial pyroptosis. NLRP3 deficiency can significantly reduce pyroptosis in SAH mice. Moreover, CXCR4 inhibition can suppress NLRP3-mediated pyroptosis, NF-κB activation and NOX2 expression in vitro, and ibrutinib can abolish CXCR4-aggravated BBB damage and pyroptosis in EBI after SAH. The levels of CXCR4 in CSF of SAH patients is significantly increased, and it is positively correlated with GSDMD and IL-1β levels, and have a moderate diagnostic value for outcome at 6-month follow-up. Our findings revealed the effect of CXCR4 and P-BTK on NLRP3-mediated pyroptosis and lipid peroxidation after SAH in vivo and in vitro, and the potential diagnostic role of CXCR4 in CSF of SAH patients. Inhibition of CXCR4-BTK axis can significantly attenuate NLRP3-mediated pyroptosis and lipid peroxidation by regulating NF-κB activation in EBI after SAH.
C-X-C 趋化因子受体 4（CXCR4）在某些中枢神经系统疾病中对适应性和先天免疫系统的稳态至关重要。布鲁顿酪氨酸激酶（BTK）是一种必需的激酶，通过多种信号通路调节免疫细胞中的炎症。本研究旨在探讨 CXCR4 和 BTK 对蛛网膜下腔出血（SAH）后早期脑损伤（EBI）发病机制中的神经炎症的影响。我们的结果表明，CXCR4 和 p-BTK 的表达在体内和体外 SAH 后 24 小时显著增加。Ibrutinib 可改善 SAH 后 24 小时的神经功能缺损、BBB 破坏、脑水肿、脂质过氧化、神经炎症和神经元死亡。BTK 磷酸化抑制可促进血红素处理的促炎小胶质细胞向抗炎状态的体外转化，抑制 p-P65 表达和小胶质细胞细胞焦亡。NLRP3 缺乏可显著减少 SAH 小鼠的细胞焦亡。此外，CXCR4 抑制可抑制体外 NLRP3 介导的细胞焦亡、NF-κB 激活和 NOX2 表达，ibrutinib 可消除 CXCR4 加重的 SAH 后 EBI 的 BBB 损伤和细胞焦亡。SAH 患者 CSF 中的 CXCR4 水平显著升高，与 GSDMD 和 IL-1β 水平呈正相关，对 6 个月随访时的结局具有中等诊断价值。我们的研究结果揭示了 CXCR4 和 P-BTK 在体内和体外 SAH 后 NLRP3 介导的细胞焦亡和脂质过氧化中的作用，以及 CXCR4 在 SAH 患者 CSF 中的潜在诊断价值。抑制 CXCR4-BTK 轴可通过调节 NF-κB 激活显著减轻 SAH 后 EBI 中 NLRP3 介导的细胞焦亡和脂质过氧化。
