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Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis

Nicole D. Powell,a Erica K. Sloan,b,c Michael T. Bailey,a,d Jesusa M. G. Arevalo,e Gregory E. Miller,f Edith Chen,f Michael S. Kobor,g Brenda F. Reader,d John F. Sheridan,a,d,h,1 and Steven W. Coleb,e,i,1


Chronic exposure to adverse social environments is associated with increased risk of disease, and stress-related increases in the expression of proinflammatory genes appear to contribute to these effects. The present study identifies a biological mechanism of such effects in the ability of the sympathetic nervous system to up-regulate bone marrow production of immature, proinflammatory monocytes. These effects are mediated by β-adrenergic receptors and the myelopoietic growth factor GM-CSF, and suggest new targets for interventions to protect health in the context of chronic social stress.


Across a variety of adverse life circumstances, such as social isolation and low socioeconomic status, mammalian immune cells have been found to show a conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes. The present study examines whether such effects might stem in part from the selective up-regulation of a subpopulation of immature proinflammatory monocytes (Ly-6chigh in mice, CD16− in humans) within the circulating leukocyte pool. Transcriptome representation analyses showed relative expansion of the immature proinflammatory monocyte transcriptome in peripheral blood mononuclear cells from people subject to chronic social stress (low socioeconomic status) and mice subject to repeated social defeat. Cellular dissection of the mouse peripheral blood mononuclear cell transcriptome confirmed these results, and promoter-based bioinformatic analyses indicated increased activity of transcription factors involved in early myeloid lineage differentiation and proinflammatory effector function (PU.1, NF-κB, EGR1, MZF1, NRF2). Analysis of bone marrow hematopoiesis confirmed increased myelopoietic output of Ly-6chigh monocytes and Ly-6cintermediate granulocytes in mice subject to repeated social defeat, and these effects were blocked by pharmacologic antagonists of β-adrenoreceptors and the myelopoietic growth factor GM-CSF. These results suggest that sympathetic nervous system-induced up-regulation of myelopoiesis mediates the proinflammatory component of the leukocyte CTRA dynamic and may contribute to the increased risk of inflammation-related disease associated with adverse social conditions.


These studies identify β-adrenergic up-regulation of myelopoiesis as one molecular mechanism by which chronic stress may induce the proinflammatory CTRA gene expression dynamic

previously observed in the circulating leukocyte pool of people confronting a diverse array of adverse life circumstances .

In the present study, healthy young adults exposed to the chronic stress of low SES showed selective expansion of both the total monocyte transcriptome and the immature CD16− monocyte transcriptome within the PBMC pool. Parallel expansion of the Ly-6chigh monocyte population was observed in mice subject to a very different type of chronic social stress in RSD, which nevertheless shares with human low SES the involvement of elevated SNS catecholamine signaling .

Bioinformatic analysis of differentially expressed genes suggested increased myelopoiesis as a potential mechanism for the selective up-regulation of immature proinflammatory monocytes. Direct analyses of myelopoiesis confirmed that result and implicated a β-adrenoreceptor–mediated pathway involving the myelopoietic growth factor GM-CSF in driving RSD-induced expansion of the mouse Ly-6chigh monocyte subpopulation. These results suggest that SNS/β-adrenergic up-regulation of myelopoiesis may play a key role in mediating the proinflammatory component of the leukocyte CTRA dynamic and could potentially contribute to the increased risk of inflammatory disease observed in individuals confronting chronic social adversity .

The present findings are consistent with previous data showing that myeloid lineage immune cells and their innate effector molecules, such as proinflammatory cytokines and type I interferons, are regulated by β-adrenergic signaling  and adverse socioenvironmental conditions. These results are also consistent with previous findings that nonsocial activators of β-adrenergic signaling, such as burn-induced sepsis, can enhance monocyte differentiation. SNS induction of a “primed” or hyperreactive bias in the circulating leukocyte pool may have evolved to help the immune system anticipate wound-related bacterial infections historically associated with adverse social conditions . However, in contemporary social environments, such dynamics would needlessly undermine antiviral responses and promote chronic inflammation . In addition to identifying one general physiological mechanism of such effects, the present data imply specific molecular strategies (e.g., β-blockade) and cellular biomarkers (e.g., CD16− monocytes) that could potentially be harnessed in future studies to develop health-protective interventions.

These data clarify the basis for the proinflammatory component of the leukocyte CTRA (, but the type I IFN- and antibody-related components of the CTRA are not explained by the present monocyte dynamics and remain to be addressed in future studies. The present transcript origin analyses implicate plasmacytoid dendritic cells (pDCs) in the observed suppression of type I IFN-related genes, but TRA showed no significant reduction in pDC numbers. The IFN component of the CTRA may instead involve β-adrenergic inhibition of IFN gene expression as previously observed in vitro. However, this study’s definition of a β-adrenergic/myelopoietic pathway by which chronic stress can remodel the circulating leukocyte pool does clarify the proinflammatory component of the CTRA  and expands the range of physiological mechanisms by which adverse social environments may increase the risk of inflammation-related disease .

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