Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200434, China.
Brain Behav Immun. 2021 Feb;92:139-156. doi: 10.1016/j.bbi.2020.11.038. Epub 2020 Dec 3.
Neuroinflammation is the inflammatory responses that are involved in the pathogenesis of most neurological disorders. Glutaminase (GLS) is the enzyme that catalyzes the hydrolysis of glutamine to produce glutamate. Besides its well-known role in cellular metabolism and excitatory neurotransmission, GLS has recently been increasingly noticed to be up-regulated in activated microglia under pathological conditions. Furthermore, GLS overexpression induces microglial activation, extracellular vesicle secretion, and neuroinflammatory microenvironment formation, which, are compromised by GLS inhibitors in vitro and in vivo. These results indicate that GLS has more complicated implications in brain disease etiology than what are previously known. In this review, we introduce GLS isoforms, expression patterns in the body and the brain, and expression/activities regulation. Next, we discuss the metabolic and neurotransmission functions of GLS. Afterwards, we summarize recent findings of GLS-mediated microglial activation and pro-inflammatory extracellular vesicle secretion, which, in turns, induces neuroinflammation. Lastly, we provide a comprehensive discussion for the involvement of microglial GLS in the pathogenesis of various neurological disorders, indicating microglial GLS as a promising target to treat these diseases.
神经炎症是涉及大多数神经紊乱疾病发病机制的炎症反应。谷氨酰胺酶（GLS）是一种催化谷氨酰胺水解生成谷氨酸的酶。除了其在细胞代谢和兴奋性神经递质传递中的众所周知的作用外，GLS 最近在病理条件下被激活的小胶质细胞中被越来越多地注意到上调。此外，GLS 的过表达诱导小胶质细胞活化、细胞外囊泡分泌和神经炎症微环境形成，而 GLS 抑制剂在体外和体内均能减轻这些作用。这些结果表明，GLS 在脑疾病发病机制中的作用比以前所知的更为复杂。在这篇综述中，我们介绍了 GLS 同工酶、在体内和脑中的表达模式以及表达/活性调节。接下来，我们讨论了 GLS 的代谢和神经递质功能。然后，我们总结了最近发现的 GLS 介导的小胶质细胞活化和促炎细胞外囊泡分泌，这反过来又诱导了神经炎症。最后，我们对小胶质细胞 GLS 在各种神经紊乱疾病发病机制中的参与进行了全面讨论，表明小胶质细胞 GLS 是治疗这些疾病的有希望的靶点。
