Deficiency of Microglial Hv1 Protects Against Lipopolysaccharide‐Induced Neuroinflammation via the NF ‐ κ B Signaling Pathway and HIF1 α ‐Mediated Metabolic Reprogramming

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.