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02 20, 2017;343 77-84.

NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide.

Wei Zhu, Feng-Sheng Cao, Jun Feng, Hua-Weng Chen, Jie-Ru Wan, Qing Lu, Jian Wang
Author Information
  1. Wei Zhu: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
  2. Feng-Sheng Cao: Department of Emergency Medicine, Xiangyang Central Hospital, Xiangyang, Hubei, PR China.
  3. Jun Feng: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
  4. Hua-Weng Chen: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
  5. Jie-Ru Wan: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
  6. Qing Lu: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. Electronic address: qinglu@mail.hust.edu.cn.
  7. Jian Wang: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: jwang79@jhmi.edu.
PMID: 27923741 DOI: 10.1016/j.neuroscience.2016.11.037

Abstract

Lipopolysaccharide (LPS) might affect the central nervous system by causing neuroinflammation, which subsequently leads to brain damage and dysfunction. In this study, we evaluated the role of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation in long-term behavioral alterations of 8-week-old male C57BL/6 mice injected intraperitoneally with LPS (5mg/kg). At different time points after injection, we assessed locomotor function with a 24-point neurologic deficit scoring system and the rotarod test; assessed recognition memory with the novel object recognition test; and assessed emotional abnormality (anhedonia and behavioral despair) with the tail suspension test, forced swim test, and sucrose preference test. We also assessed protein expression of NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1 p10 in hippocampus by Western blotting; measured levels of interleukin (IL)-1β, IL-18, tumor necrosis factor α (TNFα), and IL-10 in hippocampus; measured TNFα and IL-1β in serum by ELISA; and evaluated microglial activity in hippocampus by Iba1 immunofluorescence. We found that LPS-injected mice displayed long-term depression-like behaviors and recognition memory deficit; elevated expression of NLRP3, ASC, and caspase-1 p10; increased levels of IL-1β, IL-18, and TNFα; decreased levels of IL-10; and increased microglial activation. These effects were blocked by the NLRP3 inflammasome inhibitor Ac-Tyr-Val-Ala-Asp-chloromethylketone. The results demonstrate proof of concept that NLRP3 inflammasome activation contributes to long-term behavioral alterations in LPS-exposed mice, probably through enhanced inflammation, and that NLRP3 inflammasome inhibition might alleviate peripheral and brain inflammation and thereby ameliorate long-term behavioral alterations in LPS-exposed mice.

Keywords

LPS NLRP3 inflammasome depression forced swim test recognition memory tail suspension test

References

Brain Behav Immun. 2014 Oct;41:90-100 [PMID: 24859041]
Brain. 2005 Jul;128(Pt 7):1622-33 [PMID: 15800021]
Ann Clin Transl Neurol. 2014 Apr 1;1(4):258-271 [PMID: 24741667]
CNS Neurosci Ther. 2014 Mar;20(3):294-5 [PMID: 24479787]
Mol Neurobiol. 2016 Sep;53(7):4809-20 [PMID: 26334614]
CNS Neurosci Ther. 2015 Nov;21(11):905-13 [PMID: 26494128]
Behav Brain Res. 2016 Jan 1;296:318-325 [PMID: 26416673]
Gastroenterology. 2011 Dec;141(6):1986-99 [PMID: 22005480]
Sci Rep. 2016 Jun 08;6:27711 [PMID: 27270556]
Behav Brain Res. 2016 Jul 1;307:18-24 [PMID: 27036651]
Brain Behav Immun. 2014 Feb;36:111-7 [PMID: 24513871]
J Neuroinflammation. 2011 Mar 08;8:22 [PMID: 21385433]
Mol Neurobiol. 2016 Nov;53(9):5928-5934 [PMID: 26510743]
Brain Behav Immun. 2016 May;54:140-148 [PMID: 26812118]
Br J Pharmacol. 2000 Oct;131(3):383-6 [PMID: 11015286]
Neurosci Lett. 2016 Aug 26;629:256-261 [PMID: 27276653]
Sci Rep. 2016 Apr 07;6:24166 [PMID: 27053298]
Reproduction. 2015 Aug;150(2):105-14 [PMID: 25934945]
Cell. 2010 Mar 19;140(6):821-32 [PMID: 20303873]
Mol Neurobiol. 2016 Sep;53(7):4874-82 [PMID: 26362308]
Mediators Inflamm. 2016;2016:1045657 [PMID: 26924896]
Metab Brain Dis. 2015 Jun;30(3):669-78 [PMID: 25148914]
Acta Pharmacol Sin. 2015 Aug;36(8):939-48 [PMID: 26119880]
Mol Immunol. 2015 Aug;66(2):253-62 [PMID: 25863775]
Behav Brain Res. 2006 Nov 25;175(1):43-50 [PMID: 17023061]
Biol Psychiatry. 2009 May 1;65(9):732-41 [PMID: 19150053]
Neuroscience. 2011 Jul 28;187:63-9 [PMID: 21571042]
Pharmacol Biochem Behav. 2001 Oct-Nov;70(2-3):187-92 [PMID: 11701187]
CNS Neurol Disord Drug Targets. 2013 Sep;12(6):720-5 [PMID: 24047519]
Physiol Rev. 1991 Jan;71(1):93-127 [PMID: 1986393]
Brain Behav Immun. 2015 Jan;43:98-109 [PMID: 25063709]
Front Pharmacol. 2015 Nov 05;6:262 [PMID: 26594174]
Neuropharmacology. 2002 Dec;43(8):1339-50 [PMID: 12527484]
Brain Behav Immun. 2015 May;46:293-310 [PMID: 25697396]
Nat Protoc. 2006;1(3):1306-11 [PMID: 17406415]
J Cereb Blood Flow Metab. 2011 May;31(5):1243-50 [PMID: 21102602]
Behav Neurosci. 2003 Apr;117(2):327-40 [PMID: 12708529]
Trends Neurosci. 2015 Oct;38(10):637-658 [PMID: 26442697]
J Inflamm Res. 2015 Jan 16;8:15-27 [PMID: 25653548]
J Psychiatr Res. 2013 May;47(5):611-6 [PMID: 23394815]
J Neurochem. 2004 Feb;88(3):635-46 [PMID: 14720213]
Transl Stroke Res. 2010 Mar 1;1(1):57-64 [PMID: 20596246]
J Vis Exp. 2012 Jan 29;(59):e3638 [PMID: 22314943]
J Psychopharmacol. 2009 May;23(3):295-304 [PMID: 18562439]
Front Behav Neurosci. 2013 Oct 24;7:152 [PMID: 24187535]
Biol Psychiatry. 2010 Mar 1;67(5):446-57 [PMID: 20015486]
Am J Geriatr Psychiatry. 2013 Sep;21(9):887-97 [PMID: 23567391]
Mol Psychiatry. 2014 Jun;19(6):699-709 [PMID: 24342992]
Neurobiol Aging. 2015 Mar;36(3):1439-50 [PMID: 25623334]
CNS Neurosci Ther. 2014 Feb;20(2):119-24 [PMID: 24279434]
Prog Neuropsychopharmacol Biol Psychiatry. 2004 Dec;28(8):1255-9 [PMID: 15588751]
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):664-75 [PMID: 20599581]
PLoS One. 2015 Jul 02;10(7):e0131645 [PMID: 26135738]
Cell Death Differ. 2003 Aug;10(8):881-8 [PMID: 12867995]
J Neurosci. 2005 Sep 7;25(36):8165-72 [PMID: 16148224]
Physiol Behav. 2013 Jul 2;119:145-8 [PMID: 23769689]
PLoS One. 2014 May 15;9(5):e97423 [PMID: 24831292]
Mol Neurobiol. 2017 Nov;54(9):7327-7334 [PMID: 27815837]
Int J Clin Exp Med. 2015 Apr 15;8(4):4787-94 [PMID: 26131053]

Grants

  1. R01 AT007317/NCCIH NIH HHS
  2. R01 NS078026/NINDS NIH HHS

MeSH Term

Amino Acid Chloromethyl Ketones
Animals
Anti-Inflammatory Agents
Depressive Disorder
Hippocampus
Inflammasomes
Lipopolysaccharides
Male
Memory Disorders
Mice, Inbred C57BL
Microglia
NLR Family, Pyrin Domain-Containing 3 Protein
Random Allocation

Chemicals

Amino Acid Chloromethyl Ketones
Anti-Inflammatory Agents
Inflammasomes
Lipopolysaccharides
N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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