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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 the similar circadian oscillations as seen in human.

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

Abstract

Many immune parameters show circadian rhythms over the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells which display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, while for humans they remain unclear due to 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 CXCR4 which were controlled by the intracellular HIF-lα/ARNTLl heterodimer. Furthermore, we also discovered that p38MAPK/MK2 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 10, 2017.
  • Accepted August 22, 2017.