title: High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages.
abstract: BACKGROUND
  Aseptic trauma engages the innate immune response to trigger a neuroinflammatory reaction that results in postoperative cognitive decline. The authors sought to determine whether high-mobility group box 1 protein (HMGB1), an ubiquitous nucleosomal protein, initiates this process through activation and trafficking of circulating bone marrow-derived macrophages to the brain.
  
  
  METHODS
  The effects of HMGB1 on memory (using trace fear conditioning) were tested in adult C57BL/6J male mice; separate cohorts were tested after bone marrow-derived macrophages were depleted by clodrolip. The effect of anti-HMGB1 neutralizing antibody on the inflammatory and behavioral responses to tibial surgery were investigated.
  
  
  RESULTS
  A single injection of HMGB1 caused memory decline, as evidenced by a decrease in freezing time (52 ± 11% vs. 39 ± 5%; n = 16-17); memory decline was prevented when bone marrow-derived macrophages were depleted (39 ± 5% vs. 50 ± 9%; n = 17). Disabling HMGB1 with a blocking monoclonal antibody, before surgery, reduced postoperative memory decline (52 ± 11% vs. 29 ± 5%; n = 15-16); also, hippocampal expression of monocyte chemotactic protein-1 was prevented by the neutralizing antibody (n = 6). Neither the systemic nor the hippocampal inflammatory responses to surgery occurred in mice pretreated with anti-HMGB1 neutralizing antibody (n = 6).
  
  
  CONCLUSIONS
  Postoperative neuroinflammation and cognitive decline can be prevented by abrogating the effects of HMGB1. Following the earlier characterization of the resolution of surgery-induced memory decline, the mechanisms of its initiation are now described. Together, these data may be used to preoperatively test the risk to surgical patients for the development of exaggerated and prolonged postoperative memory decline that is reflected in delirium and postoperative cognitive dysfunction, respectively.
authors.affiliation: From the Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California (S.V., V.D., M.M.), the Programme for Advanced Medical Education, Calouste Gulbenkian Foundation, Lisbon, Portugal (S.V.), INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.), and the Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York (K.J.T.).
authors.forename: Susana
authors.initials: S
authors.lastname: Vacas
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D003072:Cognition Disorders / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000633:toxicity*; D007113:Immunity, Innate; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D011897:Random Allocation
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse