Journal Article

Chronic variable stress activates hematopoietic stem cells

Zaltsman, Alex, Fricchione, Gregory L, Heidt, Timo, Weissleder, Ralph, von zur Muhlen, Constantin, Swirski, Filip K, Denninger, John, Dutta, Partha, Libby, Peter, Courties, Gabriel, Iwamoto, Yoshiko, Nahrendorf, Matthias, Bode, Christoph, Sager, Hendrik B, Lin, Charles P, Vinegoni, Claudio

2014

Overview

Activation of bone marrow hematopoietic stem cells by chronic stress raises circulating leukocyte levels and increases atherosclerotic plaque inflammation. Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis 1 , 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 reflex 3 , 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 β 3 -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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 14/19 / 59 / 692/699/75/593/2100 / Animals / Atherosclerotic plaque / Biomedicine / Bone marrow / Cancer Research / Cell Proliferation / Chemokine CXCL12 - metabolism / Chronic illnesses / Complications and side effects / Development and progression / Disease Susceptibility / Fibers / Health aspects / Heart attack / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - immunology / Humans / Immune system / Infectious Diseases / Lesions / letter / Metabolic Diseases / Mice / Molecular Medicine / Myocardial infarction / Neurosciences / Physiological aspects / Risk factors / Rodents / Stem cells / Stress / Stress (Psychology) / Stress, Psychological - immunology / Stroke (Disease) / Upstream