title: Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression.
abstract: Mitochondrial uncoupling protein 2 (UCP2) has been well characterized to control the production of reactive oxygen species (ROS) and astrocytes are the major cells responsible for the ROS production and the inflammatory responses in the brain. However, the function of UCP2 in astrocytes and the contribution of astrocytic UCP2 to depression remain undefined. Herein, we demonstrated that UCP2 knockout (KO) mice displayed aggravated depressive-like behaviors, impaired neurogenesis, and enhanced loss of astrocytes in the chronic mild stress (CMS)-induced anhedonia model of depression. We further found that UCP2 ablation significantly enhanced the activation of the nod-like receptor protein 3 (NLRP3) inflammasome in the hippocampus and in astrocytes. Furthermore, UCP2 deficiency promoted the injury of mitochondria, the generation of ROS and the physical association between thioredoxin-interacting protein (TXNIP) and NLRP3 in astrocytes. Moreover, transiently expressing exogenous UCP2 partially rescued the deleterious effects of UCP2 ablation on the astrocytes. These data indicate that UCP2 negatively regulates the activation of NLRP3 inflammasome and inhibited the ROS-TXNIP-NLRP3 pathway in astrocytes. Collectively, our findings reveal that UCP2 regulates inflammation responses in astrocytes and plays an important role in the pathogenesis of depression and that UCP2 may be a promising therapeutic target for depression.
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China.
authors: Ren-Hong
authors: RH
authors: Du
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China.
authors: Fang-Fang
authors: FF
authors: Wu
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China.
authors: Ming
authors: M
authors: Lu
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China.
authors: Xiao-Dong
authors: XD
authors: Shu
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China.
authors: Jian-Hua
authors: JH
authors: Ding
authors: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents, 1459 Laney Walker Blvd., Augusta, GA 30912, United States.
authors: Guangyu
authors: G
authors: Wu
authors: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, 101 Nongmian Road, Nanjing, Jiangsu 210029, PR China; Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China. Electronic address: ghu@njmu.edu.cn.
authors: Gang
authors: G
authors: Hu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species; C445672:Txnip protein, mouse; D000071246:Uncoupling Protein 2; D013879:Thioredoxins
keywords: Astrocyte; Depression; NLRP3 inflammasome; Reactive oxygen species; Uncoupling protein 2