title: Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge.
abstract: Acute and chronic stressors sensitize or prime the neuroinflammatory response to a subsequent peripheral or central immunologic challenge. However, the neuroimmune process(es) by which stressors prime or sensitize subsequent neuroinflammatory responses remains unclear. Prior evidence suggested that toll-like receptors (TLRs) might be involved in the mediation of primed neuroinflammatory responses, but the role of TLRs during a stressor has never been directly tested. Here, a novel TLR2 and TLR4 antagonist, OxPAPC, was used to probe the contribution of TLRs in the stress sensitization phenomenon. OxPAPC has not previously been administered to the brain, and so its action in blocking TLR2 and TLR4 action in brain was first verified. Administration of OxPAPC into the CNS prior to stress prevented the stress-induced potentiation of hippocampal pro-inflammatory response to a subsequent peripheral LPS challenge occurring 24 h later. In addition, in vivo administration of OxPAPC prior to stress prevented the sensitized pro-inflammatory response from isolated microglia following administration of LPS ex vivo, further implicating microglia as a key neuroimmune substrate that mediates stress-induced sensitized neuroinflammation.
authors.affiliation: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO 80309-0345, USA. webermd@colorado.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weber
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Frank
authors.forename: Julia L
authors.initials: JL
authors.lastname: Sobesky
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
mesh_terms: D000818:Animals; D002946:Cisterna Magna; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004597:Electroshock; D006624:Hippocampus / Q000473:pathology; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology*; D007267:Injections; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013315:Stress, Psychological / Q000276:immunology* / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine