A circadian clock in macrophages controls inflammatory immune responses
A circadian clock in macrophages controls inflammatory immune responses
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DOI：
10.1073/pnas.0906361106
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发表时间：
2009-12-15
影响因子：
11.1
通讯作者：
Maier, Bert
中科院分区：
文献类型：
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作者：
Keller, Maren;Mazuch, Jeannine;Maier, Bert
免疫系统参数的时间依赖性变化是免疫学中普遍存在的现象。生物钟被认为在多个水平上协调这些变化;然而，它们的分子基础却知之甚少。在这里，我们系统地研究了生物钟和节律性免疫功能之间的联系。我们发现，脾脏，淋巴结和腹腔巨噬细胞的小鼠含有内在的昼夜节律时钟，即使离体自主运作。这些生物钟调节炎症性先天免疫功能的昼夜节律：在不同的昼夜节律时间用细菌内毒素刺激的分离的脾细胞显示TNF-α和IL-6分泌的昼夜节律。有趣的是，我们发现这些节律不是由全身糖皮质激素变化驱动的，也不是由于检测到的脾脏细胞结构的昼夜节律波动造成的。相反，在脾巨噬细胞中操作的局部生物钟可能支配这些振荡，如在节律性原代细胞培养物中的内毒素刺激实验所示。在分子水平上，我们发现>8%的巨噬细胞转录组以昼夜节律方式振荡，包括许多重要的病原体识别和细胞因子分泌调节因子。因此，了解生物钟和免疫系统之间的相互作用可以深入了解生理和病理生理免疫功能的计时机制。
Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-alpha and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.