title: Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction.
abstract: BACKGROUND
  According to rodent models of postoperative cognitive decline, activation of the innate immune response following aseptic surgical trauma results in the elaboration of hippocampal proinflammatory cytokines, which are capable of disrupting long-term potentiation, the neurobiologic correlate of memory. The authors hypothesize that hippocampal recruitment of bone marrow-derived macrophages plays a causal role in these processes, resulting in memory dysfunction.
  
  
  METHODS
  Clodrolip injection (liposomal formulation of clodronate) before stabilized tibial fracture under general anesthesia was used to deplete bone marrow-derived macrophages. Systemic inflammation and neuroinflammation were studied on postoperative day 1, and memory in a fear-trace conditioning paradigm was assessed on postoperative day 3. CX3CR1 CCR2 mice were used to identify bone marrow-derived macrophages.
  
  
  RESULTS
  Clodrolip effectively depleted splenic CCR2 bone marrow-derived macrophages. It also attenuated the surgery-induced increase of interleukin-6 in the serum and the hippocampus, and prevented hippocampal infiltration of CCR2 cells without affecting the number of CX3CR1 microglia. It did not alter the surgery-induced increase in hippocampal monocyte chemoattractant protein-1, the recruitment signal for CCR2 cells. Clodrolip prevented surgery-induced memory dysfunction, as evidenced by a significant increase in freezing time (29% [95% CI, 21-38%] vs. 48% [95% CI, 38-58%], n = 20, P = 0.004), but did not affect memory in nonsurgical mice.
  
  
  CONCLUSIONS
  Depletion of bone marrow-derived macrophages prevents hippocampal neuroinflammation and memory dysfunction after experimental tibial fracture. These data suggest that the hippocampal recruitment of bone marrow-derived macrophages is a necessary mechanism in murine postoperative cognitive dysfunction. Interventions designed to prevent its activation and/or migration into the brain may represent a feasible preemptive strategy.
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94110, USA. degosv@gmail.com
authors: Vincent
authors: V
authors: Degos
authors: Susana
authors: S
authors: Vacas
authors: Zhenying
authors: Z
authors: Han
authors: Nico
authors: N
authors: van Rooijen
authors: Pierre
authors: P
authors: Gressens
authors: Hua
authors: H
authors: Su
authors: William L
authors: WL
authors: Young
authors: Mervyn
authors: M
authors: Maze
mesh_terms: D000818:Animals; D007113:Immunity, Innate / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011183:Postoperative Complications / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*