Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Blood. 2017 Nov 2;130(18):1995-2005. doi: 10.1182/blood-2017-04-778779. Epub 2017 Aug 29.
Many immune parameters show circadian rhythms during the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells that display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, whereas for humans they remain unclear because of the lack of a proper model. In this study, we found that consistent with their natural host species, mouse and human circulating leukocytes exhibited opposite circadian oscillations in humanized mice. This cyclic pattern of trafficking correlated well with the diurnal expression levels of C-X-C chemokine receptor 4, which were controlled by the intracellular hypoxia-inducible factor 1α/aryl hydrocarbon receptor nuclear translocator-like heterodimer. Furthermore, we also discovered that p38 mitogen-activated protein kinases/mitogen-activated 2 had opposite effects between mice and humans in generating intracellular reactive oxygen species, which subsequently regulated HIF-1α expression. In conclusion, we propose humanized mice as a robust model for human circadian studies and reveal insights on a novel molecular clock network in the human circadian rhythm.
许多免疫参数在哺乳动物的 24 小时周期中呈现出昼夜节律。最显著的昼夜节律是循环免疫细胞的数量，人类和小鼠之间呈现出相反的节律。小鼠白细胞中昼夜节律变化的生理作用和机制已经得到了很好的研究，而对于人类，由于缺乏合适的模型，其机制仍不清楚。在这项研究中，我们发现，与它们的天然宿主物种一致，小鼠和人类的循环白细胞在人源化小鼠中表现出相反的昼夜节律波动。这种循环迁移模式与 C-X-C 趋化因子受体 4 的昼夜表达水平密切相关，后者受细胞内缺氧诱导因子 1α/芳香烃受体核转位蛋白样异二聚体的调控。此外，我们还发现，p38 丝裂原活化蛋白激酶/丝裂原激活蛋白激酶 2 在产生细胞内活性氧方面对小鼠和人类具有相反的作用，进而调节 HIF-1α 的表达。总之，我们提出人源化小鼠作为研究人类昼夜节律的有力模型，并揭示了人类昼夜节律中一个新的分子时钟网络的见解。
