空军军医大学学报2026，Vol.47Issue(3)：408-415,8.DOI:10.13276/j.issn.2097-1656.2026.03.015
谷氨酰胺合成酶缺失通过琥珀酸盐/HIF-1α轴促进小胶质细胞促炎极化
Glutamine synthetase deficiency promotes pro-inflammatory polarization of microglia via the succinate/HIF-1α axis
摘要
Abstract
Objective To investigate the mechanism by which glutamine synthetase(GS)regulates the polarization of microglia(BV2 cells).Methods(1)BV2 cells were divided into control group,lipopolysaccharide(LPS)group,and IL-4 group.The protein expression levels of GS,inducible nitric oxide synthase(iNOS)and arginase-1(Arg-1)were analyzed by immunofluorescence and Western blotting.(2)GS knockdown(siRNA)BV2 cell models were established and divided into control siRNA group,control siRNA+LPS group,GS siRNA1+LPS group,GS siRNA2+LPS group,control siRNA+IL-4 group,GS siRNA1+IL-4 group and GS siRNA2+IL-4 group.The protein expression levels of iNOS,Arg-1,and hypoxia-inducible factor-1α(HIF-1α)were analyzed by Western blotting.Immunofluorescence was used to detect CD32(M1)and CD206(M2)markers.qRT-PCR was used to quantify mRNA levels of pro-inflammatory(TNF-α,IL-1β)and anti-inflammatory(IL-10,TGF-β)cytokines.Metabolite levels(α-ketoglutarate,succinate)were measured.Results①GS expression was significantly downregulated in LPS-activated M1 BV2 cells(P＜0.01),while upregulated in IL-4-induced M2 BV2 cells(P＜0.01).(2)Following GS knockdown,LPS-treated BV2 cells exhibited increased pro-inflammatory cytokine secretion and enhanced M1 polarization(iNOS upregulation,P＜0.01).(3)GS knockdown suppressed IL-4-induced M2 polarization(Arg-1 downregulation,P＜0.01).(4)GS deficiency led to decreased α-ketoglutarate,accumulated succinate,and increased HIF-1α stability in IL-4-activated BV2 cells.Conclusion GS promotes microglial polarization towards the pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype by regulating metabolic reprogramming(succinate/HIF-1α axis).This suggests GS is a potential therapeutic target for neuroinflammation intervention.关键词
谷氨酰胺合成酶/小胶质细胞/缺氧诱导因子-1α/糖酵解/神经炎症/脂多糖/琥珀酸盐/巨噬细胞激活Key words
glutamine synthetase/microglia/hypoxia-inducible factor-1α/glycolysis/neuroinflammation/lipopolysaccharide/succinate/macrophage activation分类
医药卫生引用本文复制引用
李建伟,赵元琳,王转莉,杨阳,李立宏..谷氨酰胺合成酶缺失通过琥珀酸盐/HIF-1α轴促进小胶质细胞促炎极化[J].空军军医大学学报,2026,47(3):408-415,8.基金项目
陕西省重点研发计划项目(2024SF-YBXM-210) （2024SF-YBXM-210）
