title: NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.
abstract: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression.
  
  
  
  We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model.
  
  
  
  Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1β protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1β levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation.
  
  
  
  These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Su
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China; Department of Psychiatry, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, The 81st Hospital of PLA, 34 Yanggongjing, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Gong
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lian
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Yun-Zi
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Yun-Xia
authors.initials: YX
authors.lastname: Wang
authors.affiliation: School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, China.
authors.forename: Zi-Li
authors.initials: ZL
authors.lastname: You
authors.affiliation: New Drug Safety Evaluation Center, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Feng
authors.affiliation: New Drug Safety Evaluation Center, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zong
authors.affiliation: New Drug Safety Evaluation Center, Second Military Medical University, 800 Xiangyin Road, Shanghai, China. Electronic address: newdrug@smmu.edu.cn.
authors.forename: Guo-Cai
authors.initials: GC
authors.lastname: Lu
authors.affiliation: Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China. Electronic address: cljiang@vip.163.com.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001835:Body Weight; D002908:Chronic Disease; D003866:Depressive Disorder / Q000276:immunology* / Q000473:pathology; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D005247:Feeding Behavior; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency* / Q000235:genetics; D013315:Stress, Psychological / Q000276:immunology / Q000473:pathology; D035501:Uncertainty
chemical_list: D019422:Dietary Sucrose; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: Depression; Inflammation; Interleukin-1β; Knockout; NLRP3 inflammasome; Stress