Stress Hematopoiesis

Stress and Hematopoiesis: Activation of Hematopoi­etic stem cells and Neutrophil and Monocyte Production

Stress and Hematopoiesis

A study published in Nature Medicine suggests that stress mediators may also directly activate hematopoi­etic stem cells (HSCs), which increase proliferation and differentiate into downstream progenitor cells, with the end result of an accelerated neutrophil and monocyte production.

Acute stress is known to induce a transient leukocytosis. This is explained by the prompt effect of stress mediators, such as catecholamines (CAs) on the mobilization of these cells from depots, such as the spleen or the lung, or the marginating pool in blood vessels. Characteristically, two phases are recognized after catecholamine administration: a quick (<30 min) mobilization of lymphocytes, followed by an increase in granulocyte numbers with decreasing lymphocyte numbers. Many studies have shown that catecholamines predominantly affect natural killer (NK) cell and granulocyte circulation, whereas T- and B-cell numbers remain relatively unaffected. (Benschop RJ, Rodriguez-Feuerhahn M & Schedlowski M, Brain Behav Immun, 1996, 10:77).

It is known that the bone marrow, similar to all lymphoid organs, receives extensive sympathetic/noradrenergic innervation. In 1972, JW Byron suggested that early hematopoietic progenitors may be very sensitive to small amounts of CAs and that β-adrenoceptor stimulation might serve to trigger hemopoietic stem cells into their cell cycle (Exp Cell Res 1972, 71:228-32).

It is also known that CXCL12, originating from mesenchymal stem cells, osteoblasts and endothelial, is the key factor that inhibits hematopoietic stem and progenitor cell (HSPC) prolifera­tion and migration. Recent research indicates that the HSCs’ release is regulated through circadian norepinephrine secretion by the sympathetic nervous system (SNS), and that noradrenergic signals, locally delivered by sympathetic nerves in the bone marrow are transmitted to stromal cells by the β3-adrenergic receptor (Méndez-Ferrer S et al., Nature, 2008; 452:442).

It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity.

In the Nature Medicine study, Timo Heidt and colleagues from the Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, and the University Heart Center, Freiburg, Germany demonstrated that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes.

While investigating the source of leukocytosis in mice, the authors discovered that stress activates upstream hematopoietic stem cells. Thus, mice subjected to chronic variable stress had increased numbers of leukocytes, mostly neutrophils and monocytes in the blood, and the bone marrow itself.

The investigators found that in mice exposed to stress, the catecholamine norepinephrine (noradrenaline), the primary neurotransmitter released during an increased SNS activity caused a decreased CXCL12 expression in the hematopoietic stem cell niche, and, thus, accelerated HSC proliferation. This, in turn, increased the output of neutrophils and inflammatory monocytes from the bone marrow. Of note, the investigators also found that noradrenaline levels increased in the bone marrow of stressed mice. Thus, immunoreactive staining for tyrosine hydroxylase (TH), a rate–limiting enzyme for noradrenaline synthesis, rose along blood vessels in the bone marrow.

Heidt et al., also describe the clinical implications of their results, testing the hypothesis that chronic stress may act on the bone marrow via an increased SNS activity, and, thus, increase the inflamma­tory leukocyte supply to atherosclerotic lesions.

In atherosclerosis-prone Apoe−/− mice they found that the release of inflammatory leukocytes into the circulation promoted atherosclerotic plaque inflammation, whereas the administration of a β3-adrenoreceptor antagonist decreased the number of inflammatory immune cells in the atherosclerotic lesions and limited the inflammatory process.

In conclusion, the study describes a new axis of interaction between the central nervous system, immunity and atherosclerosis. In experimental settings and mice exposed to stress, the increased SNS activity decreased CXCL12 expression in the hematopoietic stem cell niche, accelerated HSC proliferation, and enhanced neutrophil and monocyte production. These mechanisms yielded extensive release of inflammatory leukocytes into circulation and promoted plaque inflammation.

The study provides further insights into the link between stress and inflammation, and as discussed by the authors, better understanding of the SNS signaling via the β3-adrenergic receptor, and target­ing of the CXCL12-CXCR4 interaction in the bone marrow may suggest new potential therapeutic avenues.

Source: Nat Med. 2014, 20:754. doi: 10.1038/nm.3589. Epub 2014 Jun 22.
Read more: Nature Medicine