Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex3,4. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe−/− mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.
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We thank the team at the Center for Systems Biology Mouse Imaging Program, especially J. Truelove and D. Jeon, for help with imaging, M. Stein, I. Neudorfer and F. Meixner for help with the clinical study and L. Prickett-Rice, K. Folz-Donahue, M. Weglarz, M. Waring and A. Chicoine for assistance with cell sorting. We thank P. Frenette (Albert Einstein College of Medicine) and B. Lowell (Beth Israel Deaconess Medical Center) for providing Adrb3−/− mice and G. Enikolopov (Cold Spring Harbor Laboratory) for providing nestin-GFP mice. We thank the ICU team at the University Hospital Freiburg, Germany. This work was funded in part by US National Institutes of Health grants R01-HL114477, R01-HL117829 and R01-HL096576 (to M.N.) and grant HHSN268201000044C (to R.W.). T.H. and H.B.S. are funded by the Deutsche Forschungsgemeinschaft (HE-6382/1-1 to T.H. and SA1668/2-1 to H.B.S.).
The authors declare no competing financial interests.
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Heidt, T., Sager, H., Courties, G. et al. Chronic variable stress activates hematopoietic stem cells. Nat Med 20, 754–758 (2014). https://doi.org/10.1038/nm.3589
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