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

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 leukocyt...

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Veröffentlicht in:Blood 2017-11, Vol.130 (18), p.1995-2005
Hauptverfasser: Zhao, Yue, Liu, Min, Chan, Xue Ying, Tan, Sue Yee, Subramaniam, Sharrada, Fan, Yong, Loh, Eva, Chang, Kenneth Tou En, Tan, Thiam Chye, Chen, Qingfeng
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container_end_page 2005
container_issue 18
container_start_page 1995
container_title Blood
container_volume 130
creator Zhao, Yue
Liu, Min
Chan, Xue Ying
Tan, Sue Yee
Subramaniam, Sharrada
Fan, Yong
Loh, Eva
Chang, Kenneth Tou En
Tan, Thiam Chye
Chen, Qingfeng
description 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. •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. [Display omitted]
doi_str_mv 10.1182/blood-2017-04-778779
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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. •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. 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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. •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. 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subjects Animals
Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism
Cell Movement
Chemokine CXCL12 - metabolism
Circadian Rhythm - physiology
Humans
Jet Lag Syndrome - physiopathology
Leukocytes - physiology
Mice
Models, Biological
p38 Mitogen-Activated Protein Kinases - metabolism
Reactive Oxygen Species - metabolism
Receptors, CXCR4 - metabolism
title Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice
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