title: Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor.
abstract: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1β and depressive behavioral responses to stress.
  
  
  
  The influence of acute restraint stress on extracellular ATP, glutamate, IL-1β, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1β and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice.
  
  
  
  Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1β; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1β and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress.
  
  
  
  These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Fumika
authors.initials: F
authors.lastname: Sakaue
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dutheil
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mounira
authors.initials: M
authors.lastname: Banasr
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Physiology and Pharmacology, Des Moines University, Des Moines, Iowa.
authors.forename: Vanja
authors.initials: V
authors.lastname: Duric
authors.affiliation: Division of Neuropsychiatry, Tottori University, Tottori, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yamanashi
authors.affiliation: Division of Neuropsychiatry, Tottori University, Tottori, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Kurt
authors.initials: K
authors.lastname: Rasmussen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Andrew
authors.initials: A
authors.lastname: Glasebrook
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Anja
authors.initials: A
authors.lastname: Koester
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey.
authors.forename: Dekun
authors.initials: D
authors.lastname: Song
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey.
authors.forename: Stevin
authors.initials: S
authors.lastname: Zorn
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey.
authors.forename: Gennady
authors.initials: G
authors.lastname: Smagin
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Electronic address: ronald.duman@yale.edu.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D059445:Anhedonia / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D003863:Depression / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D058912:Purinergic P2Y Receptor Agonists / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058473:Receptors, Purinergic P2Y2; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate
keywords: ATP; Depression; IL-1β; NLRP3 inflammasome; P2X7; Stress