title: Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression.
abstract: BACKGROUND
  Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Fluoxetine, a widely used antidepressant, has been shown to have potential antiinflammatory activity, but the underlying mechanisms remain obscure.
  
  
  METHODS
  We used a chronic mild stress model and cultured primary macrophage/microglia to investigate the effects of fluoxetine on NLRP3 inflammasome and its underlying mechanisms.
  
  
  RESULTS
  We demonstrated that fluoxetine significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central microglia. We further found that ﬂuoxetine reduced reactive oxygen species production, attenuated the phosphorylation of double-stranded RNA-dependent protein kinase, and inhibited the association of protein kinase with NLRP3. These data indicate that fluoxetine inhibits the activation of NLRP3 inflammasome via downregulating reactive oxygen species-protein kinase-NLRP3 signaling pathway. Correspondingly, in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior.
  
  
  CONCLUSIONS
  Our findings reveal that fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the potential clinical use of fluoxetine in NLRP3 inflammasome-driven inflammatory diseases such as depression.
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu).
authors.forename: Ren-Hong
authors.initials: RH
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu).
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu).
authors.forename: Xi-Yang
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu).
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu).
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Neurogeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, P.R. China (Drs Du, Tan, Sun, Lu, Ding, and Hu); Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China (Dr Hu). ghu@njmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
keywords: NLRP3 inflammasome; depression; double-stranded RNA-dependent protein kinase; fluoxetine; reactive oxygen species