Circadian rhythm disorders elevate macrophages cytokines release and promote multiple tissues/organs dysfunction in mice

Background:Circadian rhythm disorders are severe threats to human health. The negative impact of circadian rhythm disorders on tissues/organs has not been systematically analyzed. Therefore, there is an urgent need to evaluate the damage caused by circadian rhythm disorders and explore the possible mechanisms.

Methods:Six-week-old male mice were divided into the control (Con) group (normal circadian rhythm), L24 group (constant light), D12L12 group (weekly shift light/dark cycle), and D24 group (constant dark). Body weight was recorded every 10 days. Ninety days after model construction, the serum lipid and cytokine level, liver function, fat accumulation, carotid artery stenosis, and cardiomyopathological changes were detected in mice. Macrophages in the liver, subscapular fat, and heart tissues were labeled with immunofluorescence staining. Mouse peritoneal macrophages were then isolated. Inflammatory cytokine levels were measured in the macrophage supernatant. The ability of macrophages to form foam cells was also tested. The supernatant from macrophages in different groups was added to AML12 (hepatocytes), 3T3-L1 (preadipocytes), or HL-1 (cardiomyocytes). Effects of conditioned media on recipient cells were determined.

Results:Body weight, serum lipids and cytokines, subscapular fat accumulation, liver enzymes, carotid artery stenosis, and myocardial fibrosis levels of the L24, D12L12, and D24 groups mice were significantly higher than those in the Con group. Macrophages were significantly increased in the liver, heart, and subscapular fat of mice with circadian rhythmdisorders. Cytokine secretion by peritoneal macrophages was enhanced in the L24, D12L12, and D24 groups. Under oxidized low density lipoprotein (oxLDL) stimulation, macrophages with circadian rhythm disorders are more likely to form foam cells. Conditioned media from the L24, D12L12, and D24 groups significantly promoted AML12 apoptosis and lipid intake, accelerated the adipogenic differentiation of 3T3-L1, and up-regulated collagen I in HL-1.

Conclusion:These findings reveal that macrophages are increased in the tissues/organs under circadian rhythm disorders, and these macrophages could aggravate obesity, promote liver disease, accelerate atherosclerosis, and increase myocardial fibrosis through the paracrine effect.

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