Hellenthal Katharina E M, Thomas Katharina, Ludwig Nadine, Cappenberg Anika, Schemmelmann Lena, Tekath Tobias, Margraf Andreas, Mersmann Sina, Henke Katharina, Rossaint Jan, Zarbock Alexander, Amini Wida
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany.
Department of Cardiothoracic Surgery, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany.
J Leukoc Biol. 2025 Mar 14;117(3). doi: 10.1093/jleuko/qiae243.
During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprograming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation.
在无菌性炎症期间，组织损伤会诱导中性粒细胞过度活化并浸润到组织中，它们在其中对器官功能障碍起着关键作用。严格调控中性粒细胞的迁移及其效应功能对于防止过度的免疫反应至关重要。与其他白细胞相比，中性粒细胞消耗更多的谷氨酰胺，谷氨酰胺是人体血液中最丰富的游离α-氨基酸。然而，在炎症条件下，身体的需求超过了其产生足够量谷氨酰胺的能力。本研究调查了谷氨酰胺对中性粒细胞募集及其关键效应功能的影响。谷氨酰胺处理通过在体外调节β2整合素活性和趋化作用有效地降低了中性粒细胞的活化。在肾缺血-再灌注损伤诱导的无菌性炎症小鼠体内模型中，给予谷氨酰胺显著减弱了中性粒细胞向受损肾脏的募集。转录组分析显示，谷氨酰胺可诱导小鼠中性粒细胞的转录组重编程，从而改善线粒体功能和谷胱甘肽代谢。此外，谷氨酰胺影响中性粒细胞的关键效应功能，导致活性氧产生减少和中性粒细胞胞外陷阱形成。从机制上讲，我们使用转谷氨酰胺酶2抑制剂确定转谷氨酰胺酶2是谷氨酰胺对中性粒细胞作用的下游介质。总之，我们的研究结果表明，谷氨酰胺可减少中性粒细胞的活化和募集，从而确定谷氨酰胺是在无菌性炎症期间抑制过度中性粒细胞反应的有效手段。
