Yue Zhao1, Min Liu1, Xue Ying Chan1, Sue Yee Tan1, Sharrada Subramaniam1, Yong Fan2, Eva Loh3, Kenneth Tou En Chang3,4, Thiam Chye Tan4,5, Qingfeng Chen1,2,6,*.
1 Institute of Molecular and Cell Biology, Agency for Science,
Technology and Research (A*STAR), Singapore.
2 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
3 Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, 229899, Singapore.
4 Duke-NUS Graduate Medical School, 169857, Singapore.
5 Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, 229899, Singapore.
6 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore
* Corresponding author: Qingfeng Chen. E-mail: firstname.lastname@example.org
Published in Blood, 30 August 2017.
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.
Figure legend: Sketch map of molecular control of circadian rhythm in mouse and human leukocytes.Mouse and human leukocytes can be stimulated by the physiological stress related to light-phase during the day time. Subsequently, p38MAPK/MK2 is activated by phosphorylation. The downstream ROS levels respond differentially to p38MAPK/MK2 activation due to the possible opposite functions of MK2 between mouse and human. ROS positively correlates to the binding capacity of HIF-1α/ARNTL1/CLOCK complex on the promoter of CXCR4, which regulates the expression of CXCR4 and results in the opposite circadian oscillation between mouse and human leukocytes. Our work also highlights that human immune system in humanized mice carries human specific functions.
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