Dysregulation of inflammatory responses by chronic circadian disruption.
Dysregulation of inflammatory responses by chronic circadian disruption.
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DOI：
10.4049/jimmunol.1001026
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Davidson AJ
中科院分区：
文献类型：
--
作者：
Castanon-Cervantes O;Wu M;Ehlen JC;Paul K;Gamble KL;Johnson RL;Besing RC;Menaker M;Gewirtz AT;Davidson AJ
昼夜节律调节几乎所有哺乳动物的生理过程。在动物模型中，轮班工作或慢性时差反应期间昼夜节律的慢性破坏会导致多种疾病的风险增加。轮班工人和实验模型中的许多病症都具有炎症的共同危险因素。在这里，我们证明实验诱导的昼夜节律紊乱改变了先天免疫反应。在连续 4 周每周 6 小时的明暗时间表提前后，LPS 诱导的内毒素休克被放大，导致体温过低和死亡，死亡率为 89%，而未转换的对照小鼠死亡率为 21%。这可能是由于转移动物接受脂多糖治疗后促炎细胞因子的释放增加。从转移小鼠身上采集的分离的腹膜巨噬细胞在体外对脂多糖表现出类似的增强反应，表明这些细胞是时差反应的目标。众所周知，睡眠不足和压力会改变免疫功能，并且是我们所描述的影响的潜在介质。然而，接受轮班安排的小鼠的多导睡眠图记录显示，没有睡眠损失，轮班小鼠的压力测量也没有改变。相比之下，我们观察到慢性时差反应后小鼠的中央时钟、肝脏、胸腺和腹膜巨噬细胞中时钟基因的表达节律发生改变或消失。我们得出的结论是，昼夜节律紊乱与时差相关的先天免疫系统失调有关，但与睡眠不足或压力无关。这种免疫变化可能是轮班工作对健康产生多种负面影响的常见机制。
Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. Here we show that experimentally-induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified leading to hypothermia and death after 4 consecutive weekly 6h phase-advances of the light-dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of pro-inflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related disregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work.
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