Timo Heidt 1 , Hendrik B. Sager 1 , Gabriel Courties 1 , Partha Dutta 1 , Yoshiko Iwamoto 1 , Alex Zaltsman 1 , Constantin von zur Muhlen 2 , Christoph Bode 2 , Gregory L. Fricchione 3 , 4 , John Denninger 3 , 4 , Charles P. Lin 1 , Claudio Vinegoni 1 , Peter Libby 5 , Filip K. Swirski 1 , Ralph Weissleder 1 , 6 , Matthias Nahrendorf 1
22 June 2014
Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis 1, 2 . While incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known crosstalk 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 reflex 3, 4 . It remains unknown however if chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive 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. Sympathetic nerve fibers release surplus noradrenaline, which uses the β 3 adrenergic receptor to signal bone marrow niche cells to decrease CXCL12 levels. Consequently, elevated hematopoietic stem cell proliferation increases output of neutrophils and inflammatory monocytes. When atherosclerosis–prone ApoE −/− mice encounter chronic stress, accelerated hematopoiesis promotes plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.