title: Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.
abstract: Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Marta
authors.initials: M
authors.lastname: Pardo
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
authors.forename: Rubia de Souza
authors.initials: RS
authors.lastname: Armini
authors.affiliation: Centro de Investigaciones Biologicas-CSIC, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Laboratoire Génomique, Bioinformatique et Applications, EA4627, Conservatoire National des Arts et Métiers, 75003 Paris, France.
authors.forename: Hadley
authors.initials: H
authors.lastname: Mouhsine
authors.affiliation: Laboratoire Génomique, Bioinformatique et Applications, EA4627, Conservatoire National des Arts et Métiers, 75003 Paris, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Zagury
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States. Electronic address: rjope@med.miami.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States. Electronic address: ebeurel@med.miami.edu.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Beurel
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005473:Fluoxetine; D038362:Glycogen Synthase Kinase 3
keywords: Depression; Fluoxetine; Glycogen synthase kinase-3; Neuroinflammation; Stress; Toll-like receptor 4