Depletion of Bone Marrow-derived Macrophages Perturbs the Innate Immune Response to Surgery and Reduces Postoperative Memory Dysfunction

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 feartrace conditioning paradigm was assessed on postoperative day 3. CX3CR1(GFP/+) CCR2(RFP/+) 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. Conclusion: 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.