• Masaaki Iwata, Kristie T Ota, Xiao-Yuan Li, Fumika Sakaue, Nanxin Li, Sophie Dutheil, Mounira Banasr, Vanja Duric, Takehiko Yamanashi, Koichi Kaneko, Kurt Rasmussen, Andrew Glasebrook, Anja Koester, Dekun Song, Kenneth A Jones, Stevin Zorn, Gennady Smagin, and Ronald S Duman.
• Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
• Biol. Psychiatry. 2016 Jul 1; 80 (1): 12-22.

BackgroundThe 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.MethodsThe 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.ResultsAcute 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.ConclusionsThese 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.Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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