title: NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide.
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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Emergency Medicine, Xiangyang Central Hospital, Xiangyang, Hubei, PR China.
authors.forename: Feng-Sheng
authors.initials: FS
authors.lastname: Cao
authors.affiliation: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Hua-Weng
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Jie-Ru
authors.initials: JR
authors.lastname: Wan
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008569:Memory Disorders / Q000178:diet therapy / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011897:Random Allocation
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000893:Anti-Inflammatory Agents; D058847:Inflammasomes; D008070:Lipopolysaccharides; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: LPS; NLRP3 inflammasome; depression; forced swim test; recognition memory; tail suspension test