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Updated: May 14, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative
Vincent Degos1, Susana Vacas, Zhenying Han
1Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94110, USA. degosv@gmail.com
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.
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.
Insights
Bone marrow-derived macrophages contribute to memory loss after surgery. Depleting these cells prevented cognitive dysfunction and hippocampal inflammation in mice, suggesting a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Surgical Research
Background:
- Postoperative cognitive decline is linked to innate immune response and hippocampal cytokine release.
- Bone marrow-derived macrophages are hypothesized to play a causal role in surgery-induced memory dysfunction.
Purpose of the Study:
- To investigate the causal role of bone marrow-derived macrophages in postoperative cognitive dysfunction.
- To assess the impact of macrophage depletion on neuroinflammation and memory after surgical trauma.
Main Methods:
- Bone marrow-derived macrophages were depleted using clodrolip injection before tibial fracture surgery in mice.
- Systemic and neuroinflammation were measured, and memory was assessed using a fear-trace conditioning paradigm.
- CX3CR1 CCR2 mice were used to identify specific macrophage populations.
Main Results:
- Clodrolip effectively depleted splenic macrophages and reduced IL-6 levels in serum and hippocampus.
- Macrophage depletion prevented surgery-induced memory deficits and hippocampal infiltration of CCR2 cells.
- No significant changes were observed in non-surgical mice or in hippocampal MCP-1 levels.
Conclusions:
- Depletion of bone marrow-derived macrophages mitigates hippocampal neuroinflammation and memory impairment following experimental fracture.
- These findings highlight the critical role of macrophage recruitment in murine postoperative cognitive dysfunction.
- Targeting macrophage activation or brain migration may offer a preemptive strategy against cognitive decline.
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