Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction.
Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction.
复制标题
骨髓来源的巨噬细胞的消耗弥漫于对手术的先天免疫反应并减少术后记忆功能障碍。
DOI：
10.1097/aln.0b013e3182834d94
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发表时间：
2013-03
期刊：
影响因子：
8.8
通讯作者：
Maze M
中科院分区：
文献类型：
--
作者：
Degos V;Vacas S;Han Z;van Rooijen N;Gressens P;Su H;Young WL;Maze M
根据术后认知能力下降的啮齿动物模型，无菌手术创伤后先天免疫反应的激活导致海马促炎细胞因子的产生，这些细胞因子能够破坏长时程增强，这是记忆的神经生物学相关性。我们推测海马招募骨髓源性（BMD）巨噬细胞在这些过程中起着因果作用，导致记忆功能障碍。在全身麻醉下稳定胫骨骨折之前，使用Clodrolip注射液（氯膦酸盐的脂质体制剂）消耗BMD巨噬细胞。在术后第1天研究全身和神经炎症，并在术后第3天评估恐惧痕迹条件反射范式中的记忆。CX 3CR 1GFP/+ CCR 2 RFP/+小鼠用于鉴定BMD巨噬细胞。Clodrolip有效地耗尽了脾CCR 2 + BMD巨噬细胞。它还减弱了手术诱导的血清和海马中白细胞介素-6的增加，并防止了CCR 2+细胞的海马浸润，而不影响CX 3CR 1+小胶质细胞的数量。它没有改变手术诱导的海马MCP-1的增加，这是CCR 2+细胞的募集信号。Clodrolip可预防手术诱导的记忆功能障碍，表现为冻结时间显著增加（29%，95% CI：21 - 38% vs. 48%，95% CI：38 - 58%，n= 20，P = 0.004），但不影响非手术小鼠的记忆。实验性胫骨骨折后BMD巨噬细胞的耗竭可预防海马神经炎症和记忆功能障碍。这些数据表明，海马募集BMD巨噬细胞是小鼠术后认知功能障碍的必要机制。旨在防止其激活和/或迁移到大脑中的干预措施可能是一种可行的先发制人的策略。
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. We hypothesize that hippocampal recruitment of bone marrow-derived (BMD) macrophages plays a causal role in these processes, resulting in memory dysfunction. Clodrolip injection (liposomal formulation of clodronate) prior to stabilized tibial fracture under general anesthesia was used to deplete BMD macrophages. Systemic and neuroinflammation were studied on postoperative day 1, and memory in a fear-trace conditioning paradigm was assessed on postoperative day 3. CX3CR1GFP/+ CCR2RFP/+ mice were used to identify BMD macrophages. Clodrolip effectively depleted splenic CCR2+ BMD 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 MCP-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 to 38% vs. 48%, 95% CI: 38 to 58%, n= 20, P = 0.004), but did not affect memory in nonsurgical mice. Depletion of BMD macrophages prevents hippocampal neuroinflammation and memory dysfunction after experimental tibial fracture. These data suggest that the hippocampal recruitment of BMD 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.