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      Chronic variable stress activates hematopoietic stem cells

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          Abstract

          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.

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          Most cited references 53

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          A Global Measure of Perceived Stress

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            Inflammation in atherosclerosis.

             Peter Libby (2015)
            Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
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              A global measure of perceived stress.

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                Author and article information

                Affiliations
                [1 ]Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA
                [2 ]Department of Cardiology and Angiology I, University Heart Center, Freiburg, Germany
                [3 ]Division of Psychiatry and Medicine, Massachusetts General Hospital
                [4 ]Benson–Henry Institute for Mind Body Medicine, Massachusetts General Hospital
                [5 ]Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
                [6 ]Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
                Author notes
                Corresponding author: Matthias Nahrendorf Center for Systems Biology 185 Cambridge Street Boston, MA 02114 Tel: (617) 643–0500 Fax: (617) 643–6133 mnahrendorf@ 123456mgh.harvard.edu
                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                2 June 2014
                22 June 2014
                July 2014
                01 January 2015
                : 20
                : 7
                : 754-758
                NIHMS595172
                10.1038/nm.3589
                4087061
                24952646
                Categories
                Article

                Medicine

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