A good night’s sleep promotes immunity


In a recently published study in the Journal of Experimental Medicineresearchers in the United States used mouse models to understand how sleep fragmentation affects immunological responses and the epigenetic modifications of hematopoietic stem and progenitor cells (HSPCs). They also conducted a sleep restriction study in humans to determine HPSC programming and hematopoiesis.

Study: Sleep has a lasting effect on the function and diversity of hematopoietic stem cells.  Photo credit: Yuganov Konstantin / ShutterstockStudy: Sleep has a lasting effect on the function and diversity of hematopoietic stem cells. Photo credit: Yuganov Konstantin / Shutterstock

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Sleep deprivation is known to affect human health at various levels. Studies have shown that sleep is necessary for optimal immune system function and influences disease progression in cardiovascular diseases (CVD), neurodegenerative diseases and cancer. Sleep is known to play a role in modulating the synthesis of various signaling molecules for inflammation and immune responses.

Research on sleep deprivation and disease in mice has shown that adequate sleep reduces the cycling of HPSCs in the bone marrow and limits leukocytosis. It has also been observed to reduce lesions in atherosclerotic CVD in mice and humans by lowering blood levels of monocytes and neutrophils.

Despite the wealth of evidence linking sleep to various disease outcomes and overall health, chronic sleep disorders are a prevalent problem in the modern age. Recent findings suggesting that sleep disorders do not compensate for sleep disorders underscore the role of sleep in human health. However, the cellular and epigenetic mechanisms by which insufficient sleep affects the immune system remain unexplored.

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About the study

In the present study, the researchers quantified sleep and wake states and transition times by measuring electroencephalography (EEG) and electromyography (EMG) signals from the brain and muscle, respectively, in mouse models exposed to sleep fragmentation.

The epigenome of hematopoietic progenitor cells was profiled to understand stem-intrinsic mechanisms by which sleep mediates hematopoiesis. This included measuring histone deacetylase (HDAC) activity in the hematopoietic progenitor cells of sleep-disordered mice. In addition, transposase-accessible chromatin sequencing assays (ATAC-seq) were performed on mice given ordinary sleep, fragmented sleep, and fragmented sleep followed by recovery sleep.

Circulating leukocytes were analyzed by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure levels of granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), tumor necrosis factor alpha (TNFα), interleukin 6 (IL- 6) and interleukin 1 beta (IL-1β).

Results

The results reported that sleep fragmentation intensifies sleep-wake transitions, consequently increases hematopoiesis and causes histone acetylation that alters the epigenome of HSPCs in mice. During sleep recovery, the epigenetic imprinting of the HSPCs persisted, although hematopoiesis decreased, resulting in enhanced inflammatory responses to subsequent immune challenges.

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Using a multicolor fluorescence tracking system, the researchers found that hematopoietic clonal diversity decreased with disrupted sleep. The human sleep restriction studies showed an increase in blood monocytes and HSPCs and a decrease in HSPC histone acetylation. The authors believe fragmented sleep enhanced myeloid HSPC cues. The ELISA results also showed that the sleep-mediated HPSC increase is controlled by hypothalamic hypocretinergic signaling, with fragmented sleep leading to elevated IL-6 levels.

Previous research has shown that sleep disorders such as insomnia and obstructive sleep apnea (OSA) cause epigenetic changes in circulating leukocytes, the cardiovascular system, altered methylation of deoxyribonucleic acid (DNA) in liver and muscle tissue, and rapid epigenetic aging of blood leukocytes cause . The results of this study provided evidence that these epigenetic modifications are partially persisted and influence future immune function and disease pathology.

The study, based on the mouse model, showed that even after 10 weeks of recovery sleep, 16 weeks of sleep fragmentation resulted in increased levels of monocytes, hematopoietic stem cells that contain LinScale1+c kit+ (LSK) cells and plasma IL-6 and TNFα. These changes were also found to be intrinsic to hematopoietic cells, with bone marrow transfer experiments eliciting aggressive inflammatory responses and increased monocyte production and bone marrow hematopoiesis.

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Conclusions

Overall, the study results suggest that fluctuations in sleep quality and duration cause persistent epigenetic changes in HSPCs and reduce clonal hematopoietic diversity, leading to exaggerated inflammatory responses to subsequent infections. The authors believe the results underscore the importance of healthy sleep patterns early in life, which could reduce the severity of future illness, particularly in inflammatory diseases such as CVD and cancer.

While previous studies have identified genetic mutations leading to hematopoietic stem cell proliferation, the present study demonstrated that sleep deprivation-induced stress on the hematopoietic system results in similar hematopoietic stem cell proliferation and subsequent exaggerated immune responses without the presence of driver mutations.

Sleep deprivation is a chronic problem, especially among younger adults. The study underscores the importance of establishing healthy sleep patterns early in life to maintain a normally functioning immune system.

Magazine reference:

  • McAlpine, CS, Kiss, MG, Zuraikat, FM, Cheek, D, Schiroli, G, Amatullah, H, Huynh, P, Bhatti, MZ, Wong, L-P, Yates, AG, Poller, WC Mindur JE, Chan CT, Janssen H, Downey J, Singh S, Sadreyev RI, Nahrendorf M, Jeffrey KL, & Scadden DT (2022). Sleep exerts profound effects on the function and diversity of hematopoietic stem cells. Journal of Experimental Medicine, 219 (11). https://doi.org/10.1084/jem.20220081, https://rupress.org/jem/article/219/11/e20220081/213487/Sleep-exerts-lasting-effects-on-hematopoietic-stem



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