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Newly Described Neuro-immune Axis Links Sleep to Hematopoiesis and Atherosclerosis

Review of “Sleep modulates haematopoiesis and protects against atherosclerosis” from Nature by Stuart P. Atkinson

While multiple studies have linked a lack of adequate sleep to the increased risk of obesity, diabetes, cancer, cardiovascular disease [1], we know relatively little regarding the mechanisms involved. To begin to fill this knowledge gap, researchers led by Filip K. Swirski (Harvard Medical School, Boston, MA, USA) subjected atherosclerosis-prone mice to disruptions to normal sleeping patterns, and their subsequent analyses revealed a neuro-immune axis linking sleep to hematopoiesis and atherosclerosis [2]. 

McAlpine et al. discovered that sleep fragmentation [3] in atherosclerosis-prone mice (Apoe−/−) failed to alter body weight, plasma cholesterol, or glucose tolerance; however, the authors did observe an increase in the number of pro-inflammatory monocytes and the development of larger atherosclerotic lesions compared to mice with normal sleep patterns. Furthermore, the authors also reported the lower production of the stimulatory and wake-promoting neuropeptide hypocretin [4] in the lateral hypothalamus of the brain. Fascinatingly, the sleep fragmentation-induced reduction in hypocretin expression promoted an increase in bone marrow myeloid-biased hematopoiesis (including monocytes) by promoting the production of colony stimulating factor 1 (CSF1) [5] by hypocretin-receptor (Hcrtr1)-positive bone marrow-resident pre-neutrophils that lie in close proximity to hematopoietic progenitors [6].

In further support of this mechanism, the authors demonstrated how hypocretin-null or hematopoietic Hcrtr1-null mice exhibit substantial numbers of monocytes in the blood and significantly accelerated atherosclerosis. Furthermore, sleep-disrupted mice with CSF1 deficiency in the hematopoietic system or sleep-disrupted mice supplemented with hypocretin displayed reduced numbers of circulating monocytes and smaller atherosclerotic lesions.

Overall, the authors suggest that undisturbed sleep protects against atherosclerosis by allowing the proper release of the hippocampal hormone hypocretin, which in turn limits CSF1 production by pre-neutrophils to limit hematopoiesis and atherosclerosis. 

Does this newly described neuro-immune axis represent a druggable target to reduce cardiovascular disease in human patients? Stay tuned to the Stem Cells Portal to find out!


  1. Cappuccio FP, Cooper D, D'Elia L, et al., Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. European Heart Journal 2011;32:1484-1492.
  2. McAlpine CS, Kiss MG, Rattik S, et al., Sleep modulates haematopoiesis and protects against atherosclerosis. Nature 2019;566:383-387.
  3. Carreras A, Zhang SX, Peris E, et al., Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice. Sleep 2014;37:1817-24.
  4. Scammell TE, Arrigoni E, and Lipton JO, Neural Circuitry of Wakefulness and Sleep. Neuron 2017;93:747-765.
  5. Mossadegh-Keller N, Sarrazin S, Kandalla PK, et al., M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 2013;497:239-43.
  6. Evrard M, Kwok IWH, Chong SZ, et al., Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions. Immunity 2018;48:364-379 e8.