Sun Lingbin, Wang Xihua, Guan Shuyuan, Zhang Ping, Chen Dongling, Luo Tao
Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, China.
Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China.
FASEB J. 2025 Sep 15;39(17):e70894. doi: 10.1096/fj.202402271RRR.
Neuroinflammation plays a pivotal role in the initiation and progression of cognitive impairments. Hv1 channels have been implicated in proton extrusion, microglial activation, and neuroinflammation onset. Despite this, the specific mechanisms by which Hv1 deficiency mitigates neuroinflammation and its impact on pathophysiological processes are not fully understood. In this study, we investigated the role of Hv1 in LPS-induced hippocampal inflammation and cognitive deficits. Utilizing both knockout/knockdown and overexpression methodologies, we uncovered Hv1's contribution to neuroinflammatory processes. Our findings reveal that Hv1 loss exerts dual protective effects against LPS-induced neuroinflammation through NF-κB-mediated cytokine production and PI3K/Akt/HIF1α-mediated aerobic glycolysis, as evidenced by RNA sequencing and metabolomics analysis. Given the pivotal function of NF-κB in these responses, we observed a decrease in NF-κB activation and a reduction in the production of pro-inflammatory mediators in microglia with Hv1 deficiency. Conversely, the luciferase reporter assay and EMSA revealed that Hv1 overexpression augments NF-κB signaling. Furthermore, Hv1 deficiency resulted in reduced HIF1α expression and downregulation of its target genes, including HK2 and PFKFB3, thereby inhibiting aerobic glycolysis. In vivo results reveal a distinct microglial Hv1 role in regulating microglial metabolic reprogramming and neuroinflammation in cognitive deficits, suggesting Hv1 as a potential therapeutic target for neuroinflammation mediated by microglia, especially in the context of NF-κB dysregulation. Our findings highlight the significance of targeting aerobic glycolysis in the regulation of cognitive impairments. Additionally, our research provides novel insights into Hv1's regulatory influence on neuroinflammation via NF-κB signaling and metabolic reprogramming pathways.
神经炎症在认知障碍的发生和发展中起关键作用。Hv1通道与质子排出、小胶质细胞激活及神经炎症的发生有关。尽管如此，Hv1缺乏减轻神经炎症的具体机制及其对病理生理过程的影响仍未完全明确。在本研究中，我们调查了Hv1在脂多糖（LPS）诱导的海马炎症和认知缺陷中的作用。利用基因敲除/敲低和过表达方法，我们揭示了Hv1对神经炎症过程的贡献。我们的研究结果表明，通过RNA测序和代谢组学分析证明，Hv1缺失通过NF-κB介导的细胞因子产生和PI3K/Akt/HIF1α介导的有氧糖酵解对LPS诱导的神经炎症发挥双重保护作用。鉴于NF-κB在这些反应中的关键作用，我们观察到Hv1缺乏时小胶质细胞中NF-κB激活减少，促炎介质产生减少。相反，荧光素酶报告基因检测和电泳迁移率变动分析表明，Hv1过表达增强NF-κB信号传导。此外，Hv1缺乏导致HIF1α表达降低及其靶基因（包括HK2和PFKFB3）下调，从而抑制有氧糖酵解。体内结果揭示了小胶质细胞Hv1在调节认知缺陷中的小胶质细胞代谢重编程和神经炎症方面具有独特作用，表明Hv1是小胶质细胞介导的神经炎症的潜在治疗靶点，特别是在NF-κB失调的情况下。我们的研究结果强调了靶向有氧糖酵解在调节认知障碍中的重要性。此外，我们的研究为Hv1通过NF-κB信号传导和代谢重编程途径对神经炎症的调节影响提供了新的见解。
