title: Chronic variable stress activates hematopoietic stem cells.
abstract: Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. 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. 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.
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Timo
authors: T
authors: Heidt
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Hendrik B
authors: HB
authors: Sager
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Gabriel
authors: G
authors: Courties
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Partha
authors: P
authors: Dutta
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Yoshiko
authors: Y
authors: Iwamoto
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Alex
authors: A
authors: Zaltsman
authors: Department of Cardiology and Angiology I, University Heart Center, Freiburg, Germany.
authors: Constantin
authors: C
authors: von Zur Muhlen
authors: Department of Cardiology and Angiology I, University Heart Center, Freiburg, Germany.
authors: Christoph
authors: C
authors: Bode
authors: Division of Psychiatry and Medicine, Massachusetts General Hospital.|Benson-Henry Institute for Mind Body Medicine, Massachusetts General Hospital.
authors: Gregory L
authors: GL
authors: Fricchione
authors: Division of Psychiatry and Medicine, Massachusetts General Hospital.|Benson-Henry Institute for Mind Body Medicine, Massachusetts General Hospital.
authors: John
authors: J
authors: Denninger
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Charles P
authors: CP
authors: Lin
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Claudio
authors: C
authors: Vinegoni
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors: Peter
authors: P
authors: Libby
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Filip K
authors: FK
authors: Swirski
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.|Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors: Ralph
authors: R
authors: Weissleder
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
authors: Matthias
authors: M
authors: Nahrendorf
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D004198:Disease Susceptibility; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D051379:Mice; D013315:Stress, Psychological / Q000276:immunology*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse