title: Resolving postoperative neuroinflammation and cognitive decline.
abstract: OBJECTIVE
  Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved.
  
  
  METHODS
  C57BL/6J, Ccr2(RFP/+)Cx3cr1(GFP/+), Ikk(F/F) mice and LysM-Cre/Ikk(F/F) mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood-brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied.
  
  
  RESULTS
  Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery.
  
  
  CONCLUSIONS
  These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648.
authors.forename: Niccolò
authors.initials: N
authors.lastname: Terrando
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648.|Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars I
authors.initials: LI
authors.lastname: Eriksson
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.
authors.forename: Jae Kyu
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.affiliation: Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jonsson Fagerlund
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA.
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000008:administration & dosage; D001522:Behavior, Animal; D039481:CD11b Antigen / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control; D003213:Conditioning, Psychological / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004147:Dioxins / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005239:Fear / Q000502:physiology; D024243:HMGB1 Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D016328:NF-kappa B / Q000378:metabolism; D018722:Nicotinic Agonists / Q000008:administration & dosage; D011183:Postoperative Complications / Q000503:physiopathology*; D054390:Receptors, CCR2 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001372:Aza Compounds; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D004147:Dioxins; D024243:HMGB1 Protein; D008164:Luminescent Proteins; D016328:NF-kappa B; D018722:Nicotinic Agonists; C514026:PHA-568487E; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase