Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Oct 8;110(41):16574-9.
doi: 10.1073/pnas.1310655110. Epub 2013 Sep 23.

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

Nicole D Powell  1 , Erica K Sloan, Michael T Bailey, Jesusa M G Arevalo, Gregory E Miller, Edith Chen, Michael S Kobor, Brenda F Reader, John F Sheridan, Steven W Cole
Affiliations

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

Nicole D Powell et al. Proc Natl Acad Sci U S A. .

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-6c(high) 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-6c(high) monocytes and Ly-6c(intermediate) 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.

Keywords: immunology; social genomics.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Differential gene expression in mouse CD11b+ monocytes and PBMCs. (A) Genome-wide transcriptional profiling of (unstimulated) adherent CD11b+ spleen monocytes harvested after 6 d of RSD or HCC conditions identified 2,976 transcripts showing ≥50% difference in mean abundance across groups (n = 6 animals per condition pooled into three groups of two for microarray assay; results representative of two independent experiments). Red, overexpressed in RSD; blue, overexpressed in HCC (underexpressed in RSD). (B) Effects of RSD on gene expression in total PBMCs (black bars) and monocyte-depleted PBMCs (CD11b−, gray bars). Data represent mean fold difference (±SE) in expression of 100 genes showing greatest RSD-induced up-regulation in total PBMCs (RSD transcriptome shift; Upper) or six representative proinflammatory genes (Lower); n = 3 animals per condition in one experiment representative of three independent experiments. (C) Promoter-based bioinformatic analysis of myeloid lineage transcription factors in genes up-regulated in RSD vs. HCC monocytes (A). Data represent mean fold difference (±SE) in prevalence of transcription factor binding motifs, averaged over nine parametric combinations of promoter length and motif detection stringency. P values, two-tailed difference from null difference of 0%.
Fig. 2.
Fig. 2.
Monocyte subset prevalence in bone marrow and peripheral compartments. (A) Average prevalence (±SE) of CD11b+/Gr1+ monocytes within total spleen cells (n = 6 per condition, representative of three independent experiments). (B) Average prevalence (±SE) of Ly-6chigh cells within splenic CD11b+/Gr1+ monocyte pool (samples from A). (C) Flow cytometric quantification of Ly-6cintermediate and Ly-6chigh (horizontal axis) CD11b+ (vertical axis) mononuclear cells in spleen, blood, and bone marrow from RSD and HCC mice. Percentages represent total CD11b+/Ly-6c+ myeloid cells (monocytes + granulocytes).
Fig. 3.
Fig. 3.
Role of lineage differentiation and β-adrenergic/GM-CSF signaling. (A) Flow cytometric assessment of mixed-lineage progenitors (Pro), and erythroid (Er), lymphoid (Ly), granulocytic (Gr), and monocytic (Mo) lineage cells in bone marrow. (B) Average prevalence (±SE) of each progenitor cell type (n = 3–7 per condition, representative of three independent experiments). *P < 0.05; **P < 0.001. (C) Effect of the β-adrenergic antagonist propranolol on RSD-induced expansion of splenic Ly-6chigh monocytes. Data represent mean prevalence (±SE) of Ly-6chigh/CD11b+ cells as a percent of total splenocytes (n = 9 per condition; Pro, propranolol; Veh, vehicle). (D) Effect of propranolol on RSD-induced up-regulation of 17 proinflammatory gene transcripts in peripheral blood monocytes (Cxcl1, Cxcl2, Fos, Fosb, Fosl1, Il1a, Il1b, Il6, Jun, Junb, Jund1, Ly6c, Myd88, Ptgs1, Ptgs2, Tlr2, Tnf). Data represent mean percent difference in gene expression (RSD – HCC, ±SE) in vehicle-treated vs. propranolol-treated mice (n = 3 per condition; representative of results from four independent experiments). RSD up-regulated proinflammatory gene expression by an average 25.1% in vehicle-treated animals (P < 0.001) vs. an average −11.7% difference in propranolol-treated animals (P = 0.017). (E) Effect of GM-CSF–neutralizing antibody MP1-22E9 (or isotype control antibody) on average prevalence (±SE) of peripheral blood Ly-6chigh monocytes and Ly-6cintermediate granulocytes (as determined by flow cytometry in n = 8 animals per condition pooled across three independent experiments). (F) Parallel assessment of bone marrow CD31+/Ly-6chigh monocyte progenitors and CD31+/Ly-6cintermediate granulocyte progenitors.
Fig. 4.
Fig. 4.
Socioeconomic status and human leukocyte subsets. (A) Transcript origin analysis assessing predominate cellular sources of 387 gene transcripts found to be differentially expressed by ≥20% in genome-wide transcriptional profiling of PBMCs from 30 low-SES healthy young adults and 30 matched high-SES individuals. (B) Transcriptome representation analysis assessing prevalence of transcriptomes corresponding to major leukocyte subsets in total PBMC RNA samples. (C) Relative percent and absolute frequency of monocytes, lymphocytes, and granulocytes in circulating blood samples.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cole SW, et al. Social regulation of gene expression in human leukocytes. Genome Biol. 2007;8(9):R189. - PMC - PubMed
    1. Cole SW, Hawkley LC, Arevalo JM, Cacioppo JT. Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proc Natl Acad Sci USA. 2011;108(7):3080–3085. - PMC - PubMed
    1. Miller GE, et al. A functional genomic fingerprint of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry. 2008;64(4):266–272. - PMC - PubMed
    1. Chen E, et al. Genome-wide transcriptional profiling linked to social class in asthma. Thorax. 2009;64(1):38–43. - PMC - PubMed
    1. Chen E, Miller GE, Kobor MS, Cole SW. Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood. Mol Psychiatry. 2011;16(7):729–737. - PMC - PubMed

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources