Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice

Yue Zhao, Min Liu, Xue Ying Chan, Sue Yee Tan, Sharrada Subramaniam, Yong Fan, Eva Loh, Kenneth Tou En Chang, Thiam Chye Tan and Qingfeng Chen

Key Points

  • Human circulating leukocytes in humanized mice reproduce similar circadian oscillations as seen in humans.

  • A novel molecular clock network exhibiting opposite effects on regulating human and mouse leukocyte circadian rhythm is discovered.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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.

  • Submitted April 8, 2017.
  • Accepted August 22, 2017.
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