title: Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.
abstract: BACKGROUND
  The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue.
  
  
  METHODS
  We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated.
  
  
  RESULTS
  Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered.
  
  
  CONCLUSIONS
  These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Zi-Teng
authors.initials: ZT
authors.lastname: Zhang
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Xiu-Ming
authors.initials: XM
authors.lastname: Du
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Ma
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zong
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Ji-Kuai
authors.initials: JK
authors.lastname: Chen
authors.affiliation: Laboratory Animal Center, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Chen-Lin
authors.initials: CL
authors.lastname: Yu
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Yan-Gang
authors.initials: YG
authors.lastname: Liu
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Yong-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China. zlj6583@163.com.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, 200433, China. newdrug@smmu.edu.cn.
authors.forename: Guo-Cai
authors.initials: GC
authors.lastname: Lu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005221:Fatigue / Q000139:chemically induced* / Q000503:physiopathology* / Q000523:psychology; D015673:Fatigue Syndrome, Chronic / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D058847:Inflammasomes / Q000187:drug effects*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000187:drug effects*; D013315:Stress, Psychological / Q000503:physiopathology; D013550:Swimming / Q000523:psychology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: Chronic fatigue syndrome; IL-1β; LPS; NLRP3 inflammasome; NLRP3 knockout mice