Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Department of Anaesthesiology, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200070, China; Translational Research Institute of Brain and Brain-Like Intelligence Affiliated to Tongji University School of Medicine, Shanghai 200070, China.
Brain Behav Immun. 2022 Jan;99:231-245. doi: 10.1016/j.bbi.2021.10.009. Epub 2021 Oct 19.
Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.
谷氨酰胺酶 1（GLS1）最近被报道在小胶质细胞中表达，并在神经炎症中发挥关键作用。在抑郁症患者死后的前额叶皮层中观察到 GLS1mRNA 表达水平的显著增加以及神经炎症途径。为了研究小胶质细胞 GLS1 在抑郁症和神经炎症中的功能，我们生成了转基因小鼠（GLS1 cKO），在小胶质细胞中后天缺失 GLS1，以检测脂多糖（LPS）诱导的抑郁症模型中的变化。在 GLS1 cKO 小鼠中，LPS 诱导的焦虑/抑郁样行为减弱，同时前额叶皮层中的促炎细胞因子显著减少，小胶质细胞形态异常。小胶质细胞中 GLSl 缺乏导致的神经炎症减少是由于反应性星形胶质细胞减少所致，因为 GLSl 缺乏会增加小胶质细胞释放的细胞外囊泡中的 miR-666-3p 和 miR-7115-3p 水平，从而通过抑制 Serpina3n 表达抑制星形胶质细胞激活。总之，我们的数据揭示了 GLS1 在神经炎症中的新机制，靶向小胶质细胞中的 GLS1 可能是缓解神经炎症相关抑郁症和其他疾病的新策略。
