Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved August 21, 2013 (received for review June 5, 2013)
Significance
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.
Abstract
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.
Data Availability
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE28830, GSE47153, and GSE47154).
Acknowledgments
We thank the Genome Quebec Innovation Centre, the University of California, Los Angeles (UCLA) DNA Microarray Core, and the UCLA Neuroscience Genomics Core for performing microarray assays. This research was supported by National Institutes of Health Grants HD058502, MH46801, MH093473, DE014320, CA116778, AG033590, and AG107265; the Mind, Body, Brain, and Health Initiative of the John D. and Catherine T. MacArthur Foundation; the British Colombia Ministry of Child and Family Development via the Human Early Learning Partnership; and the Allergy, Genes, and Environment Research Network.
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References
1
SW Cole, et al., Social regulation of gene expression in human leukocytes. Genome Biol 8, R189 (2007).
2
SW Cole, LC Hawkley, JM Arevalo, JT Cacioppo, Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proc Natl Acad Sci USA 108, 3080–3085 (2011).
3
GE Miller, et al., A functional genomic fingerprint of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry 64, 266–272 (2008).
4
E Chen, et al., Genome-wide transcriptional profiling linked to social class in asthma. Thorax 64, 38–43 (2009).
5
E Chen, GE Miller, MS Kobor, SW Cole, Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood. Mol Psychiatry 16, 729–737 (2011).
6
GE Miller, et al., Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci USA 106, 14716–14721 (2009).
7
SW Cole, et al., Computational identification of gene-social environment interaction at the human IL6 locus. Proc Natl Acad Sci USA 107, 5681–5686 (2010).
8
A O’Donovan, et al., Transcriptional control of monocyte gene expression in post-traumatic stress disorder. Dis Markers 30, 123–132 (2011).
9
MH Antoni, et al., Transcriptional modulation of human leukocytes by cognitive-behavioral stress management in women undergoing treatment for breast cancer. Biol Psychiatry 71, 366–372 (2012).
10
EK Sloan, et al., Social stress enhances sympathetic innervation of primate lymph nodes: Mechanisms and implications for viral pathogenesis. J Neurosci 27, 8857–8865 (2007).
11
EK Sloan, et al., The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70, 7042–7052 (2010).
12
J Tung, et al., Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proc Natl Acad Sci USA 109, 6490–6495 (2012).
13
SW Cole, et al., Transcriptional modulation of the developing immune system by early life social adversity. Proc Natl Acad Sci USA 109, 20578–20583 (2012).
14
SW Cole, Social regulation of human gene expression. Curr Dir Psychol Sci 18, 132–137 (2009).
15
G Miller, E Chen, SW Cole, Health psychology: Developing biologically plausible models linking the social world and physical health. Annu Rev Psychol 60, 501–524 (2009).
16
SW Cole, Elevating the perspective on human stress genomics. Psychoneuroendocrinology 35, 955–962 (2010).
17
MR Irwin, SW Cole, Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11, 625–632 (2011).
18
CE Finch The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Life Spans (Academic, Burlington, MA, 2007).
19
LF Berkman, I Kawachi Social Epidemiology (Oxford Univ Press, New York, 2000).
20
J Banks, M Marmot, Z Oldfield, JP Smith, Disease and disadvantage in the United States and in England. JAMA 295, 2037–2045 (2006).
21
H Engler, MT Bailey, A Engler, JF Sheridan, Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen. J Neuroimmunol 148, 106–115 (2004).
22
FS Dhabhar, WB Malarkey, E Neri, BS McEwen, Stress-induced redistribution of immune cells—from barracks to boulevards to battlefields: A tale of three hormones—Curt Richter Award winner. Psychoneuroendocrinology 37, 1345–1368 (2012).
23
F Geissmann, et al., Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).
24
IJ Elenkov, RL Wilder, GP Chrousos, ES Vizi, The sympathetic nerve—an integrative interface between two supersystems: The brain and the immune system. Pharmacol Rev 52, 595–638 (2000).
25
Y Katayama, et al., Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).
26
S Méndez-Ferrer, D Lucas, M Battista, PS Frenette, Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).
27
KA Beiermeister, et al., Hematopoietic progenitor cell mobilization is mediated through beta-2 and beta-3 receptors after injury. J Trauma 69, 338–343 (2010).
28
Y Tang, et al., Norepinephrine modulates myelopoiesis after experimental thermal injury with sepsis. Ann Surg 233, 266–275 (2001).
29
MJ Cohen, et al., Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis. Ann Surg 240, 132–141 (2004).
30
R Avitsur, N Powell, DA Padgett, JF Sheridan, Social interactions, stress, and immunity. Immunol Allergy Clin North Am 29, 285–293 (2009).
31
JL Stark, R Avitsur, J Hunzeker, DA Padgett, JF Sheridan, Interleukin-6 and the development of social disruption-induced glucocorticoid resistance. J Neuroimmunol 124, 9–15 (2002).
32
R Avitsur, A Kavelaars, C Heijnen, JF Sheridan, Social stress and the regulation of tumor necrosis factor-alpha secretion. Brain Behav Immun 19, 311–317 (2005).
33
MT Bailey, H Engler, ND Powell, DA Padgett, JF Sheridan, Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway. Am J Physiol Regul Integr Comp Physiol 293, R1180–R1190 (2007).
34
ND Powell, et al., Repeated social defeat activates dendritic cells and enhances Toll-like receptor dependent cytokine secretion. Brain Behav Immun 23, 225–231 (2009).
35
P Dong-Newsom, ND Powell, MT Bailey, DA Padgett, JF Sheridan, Repeated social stress enhances the innate immune response to a primary HSV-1 infection in the cornea and trigeminal ganglia of Balb/c mice. Brain Behav Immun 24, 273–280 (2010).
36
ES Wohleb, et al., β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 31, 6277–6288 (2011).
37
JW Mays, et al., Influenza virus-specific immunological memory is enhanced by repeated social defeat. J Immunol 184, 2014–2025 (2010).
38
ND Powell, JW Mays, MT Bailey, ML Hanke, JF Sheridan, Immunogenic dendritic cells primed by social defeat enhance adaptive immunity to influenza A virus. Brain Behav Immun 25, 46–52 (2011).
39
JL Stark, et al., Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regul Integr Comp Physiol 280, R1799–R1805 (2001).
40
R Avitsur, JL Stark, FS Dhabhar, DA Padgett, JF Sheridan, Social disruption-induced glucocorticoid resistance: Kinetics and site specificity. J Neuroimmunol 124, 54–61 (2002).
41
N Quan, et al., Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice. J Neuroimmunol 137, 51–58 (2003).
42
H Engler, et al., Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen. Psychoneuroendocrinology 33, 108–117 (2008).
43
MT Bailey, et al., Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. J Immunol 182, 7888–7896 (2009).
44
S Gordon, PR Taylor, Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953–964 (2005).
45
MA Ingersoll, et al., Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115, e10–e19 (2010).
46
CS Robbins, FK Swirski, The multiple roles of monocyte subsets in steady state and inflammation. Cell Mol Life Sci 67, 2685–2693 (2010).
47
GW Evans, K English, The environment of poverty: Multiple stressor exposure, psychophysiological stress, and socioemotional adjustment. Child Dev 73, 1238–1248 (2002).
48
S Cohen, WJ Doyle, A Baum, Socioeconomic status is associated with stress hormones. Psychosom Med 68, 414–420 (2006).
49
D Janicki-Deverts, et al., Socioeconomic status is related to urinary catecholamines in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Psychosom Med 69, 514–520 (2007).
50
AF Valledor, FE Borràs, M Cullell-Young, A Celada, Transcription factors that regulate monocyte/macrophage differentiation. J Leukoc Biol 63, 405–417 (1998).
51
K Saeki, K Saeki, A Yuo, Distinct involvement of cAMP-response element-dependent transcriptions in functional and morphological maturation during retinoid-mediated human myeloid differentiation. J Leukoc Biol 73, 673–681 (2003).
52
D Sawka-Verhelle, et al., PE-1/METS, an antiproliferative Ets repressor factor, is induced by CREB-1/CREM-1 during macrophage differentiation. J Biol Chem 279, 17772–17784 (2004).
53
PJ Leenen, WA Slieker, M Melis, W Van Ewijk, Murine macrophage precursor characterization. I. Production, phenotype and differentiation of macrophage precursor hybrids. Eur J Immunol 20, 15–25 (1990).
54
T Nikolic, MF de Bruijn, MB Lutz, PJ Leenen, Developmental stages of myeloid dendritic cells in mouse bone marrow. Int Immunol 15, 515–524 (2003).
55
AR Abbas, et al., Immune response in silico (IRIS): Immune-specific genes identified from a compendium of microarray expression data. Genes Immun 6, 319–331 (2005).
56
ML Hanke, ND Powell, LM Stiner, MT Bailey, JF Sheridan, Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress. Brain Behav Immun 26, 1150–1159 (2012).
57
A Collado-Hidalgo, C Sung, S Cole, Adrenergic inhibition of innate anti-viral response: PKA blockade of type I interferon gene transcription mediates catecholamine support for HIV-1 replication. Brain Behav Immun 20, 552–563 (2006).
58
B Mayer, et al., Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels. Int J Cardiol 103, 182–186 (2005).
59
E Tatli, T Kurum, A controlled study of the effects of carvedilol on clinical events, left ventricular function and proinflammatory cytokines levels in patients with dilated cardiomyopathy. Can J Cardiol 21, 344–348 (2005).
60
JR Gage, et al., Beta blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production in patients with chronic heart failure. Neuroimmunomodulation 11, 173–180 (2004).
61
T Matsumura, et al., Effects of carvedilol on plasma levels of interleukin-6 and tumor necrosis factor-alpha in nine patients with dilated cardiomyopathy. J Cardiol 39, 253–257 (2002).
62
T Ohtsuka, et al., Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol 37, 412–417 (2001).
63
Y Gidron, T Armon, H Gilutz, M Huleihel, Psychological factors correlate meaningfully with percent-monocytes among acute coronary syndrome patients. Brain Behav Immun 17, 310–315 (2003).
64
JD Creswell, et al., Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: A small randomized controlled trial. Brain Behav Immun 26, 1095–1101 (2012).
65
DS Black, et al., Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology 38, 348–355 (2013).
66
AI Su, et al., A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101, 6062–6067 (2004).
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Freely available online through the PNAS open access option.
Data Availability
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE28830, GSE47153, and GSE47154).
Submission history
Published online: September 23, 2013
Published in issue: October 8, 2013
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Acknowledgments
We thank the Genome Quebec Innovation Centre, the University of California, Los Angeles (UCLA) DNA Microarray Core, and the UCLA Neuroscience Genomics Core for performing microarray assays. This research was supported by National Institutes of Health Grants HD058502, MH46801, MH093473, DE014320, CA116778, AG033590, and AG107265; the Mind, Body, Brain, and Health Initiative of the John D. and Catherine T. MacArthur Foundation; the British Colombia Ministry of Child and Family Development via the Human Early Learning Partnership; and the Allergy, Genes, and Environment Research Network.
Notes
*This Direct Submission article had a prearranged editor.
†
Social epidemiologists use “adversity” to denote health risk factors defined by objective external conditions of one’s life (e.g., low SES, bereavement, caregiving for a dying spouse) as opposed to internal subjective reactions to those conditions (e.g., stress, depression) or physiological responses (e.g., allostatic load). This presentation does not require any distinction between chronic stress and adversity, and we use the terms interchangeably.
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The authors declare no conflict of interest.
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Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis, Proc. Natl. Acad. Sci. U.S.A.
110 (41) 16574-16579,
https://doi.org/10.1073/pnas.1310655110
(2013).
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