Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin, 10117 Berlin, Germany.
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21407-12. doi: 10.1073/pnas.0906361106. Epub 2009 Dec 1.
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.
昼夜节律对免疫系统参数的影响在免疫学中是普遍存在的现象。生物钟被认为在多个层面上协调这些变化；然而，它们的分子基础还知之甚少。在这里，我们系统地研究了生物钟与节律性免疫功能之间的联系。我们表明，即使在体外，小鼠的脾脏、淋巴结和腹膜巨噬细胞中也存在内在的生物钟，这些生物钟可以自主运作。这些时钟调节炎症性先天免疫功能的昼夜节律：在不同的生物钟时间用细菌内毒素刺激分离的脾细胞会显示 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系统性糖皮质激素变化驱动的，也不是由于脾脏细胞组成的检测到的昼夜波动引起的。相反，正如在节律性原代细胞培养物中的内毒素刺激实验所表明的那样，脾脏巨噬细胞中存在的局部生物钟可能控制着这些波动。在分子水平上，我们表明，巨噬细胞转录组中有超过 8%以昼夜节律的方式波动，包括许多用于病原体识别和细胞因子分泌的重要调节剂。因此，了解生物钟与免疫系统之间的相互作用为生理和病理生理免疫功能的定时机制提供了深入了解。
