Social stress induces glucocorticoid resistance in macrophages
Abstract
Stress-induced levels of plasma glucocorticoid hormones are known to modulate leukocyte function. These experiments examined the effects of a social stressor on the responsiveness of peripheral immune cells. Male mice experienced six evening cycles of social disruption (SDR), in which an aggressive male intruder was placed into their home cage for 2 h. Although circulating corticosterone was elevated in SDR mice, they had enlarged spleens and increased numbers of splenic leukocytes. Splenocytes from SDR and control mice were cultured with lipopolysaccharide and corticosterone. Cells from SDR mice exhibited decreased sensitivity to the antiproliferative effects of corticosterone, suggesting that the peripheral immune cells were resistant to glucocorticoids. In addition, SDR cells produced more interleukin (IL)-6. To determine which cell population was affected, we used antibody-labeled magnetic beads to deplete splenocyte suspensions of B cells or macrophages. Depletion of macrophages from SDR cultures, but not depletion of B cells, abolished both the corticosterone resistance and enhanced IL-6 secretion. These findings demonstrate that a psychosocial stressor induced glucocorticoid resistance in mouse splenic macrophages.
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Chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress endotoxin-stimulated cytokine production in humans and animals.
“Support for this account has accrued in studies of humans and animals (14,17,19,20), where chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress endotoxin-stimulated cytokine production.”
From A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling (2008) · cites this paper as [19]
These findings converge with evidence from rodent studies that experimentally manipulate stressor exposure and find it diminishes sensitivity to glucocorticoid-mediated signaling in immune and nervous systems.
“These findings converge with evidence from studies of rodents, which experimentally manipulate exposure to stressors, and find that it diminishes sensitivity to glucocorticoid-mediated signaling, both in the immune and nervous systems (19,44).”
From A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling (2008) · cites this paper as [19]
Initial support for the proposition that chronic stressors bring about functional resistance to cortisol-mediated signaling has emerged in studies showing chronic stressors diminish the capacity of glucocorticoids to suppress ex vivo inflammatory cytokine production.
“Initial support for this proposition has emerged in a series of studies where chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress ex vivo inflammatory cytokine production (14,17,19,20).”
From A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling (2008) · cites this paper as [19]
The results converge with experimental studies in animals, wherein the causal influence of stressors on sensitivity to glucocorticoid signaling has been established.
“the results converge with experimental studies in animals, wherein the causal influence of stressors on sensitivity to glucocorticoid signaling has been established (19,44).”
From A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling (2008) · cites this paper as [19]
Effective down-regulation of inflammation by glucocorticoids is essential to preventing persistently elevated inflammation.
“The effective down-regulation of inflammation by glucocorticoids is essential to preventing persistently elevated (Stark et al., 2001).”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Stark et al., 2001
Animals injured during repeated social defeat exhibit glucocorticoid-resistant immune cells, systemic increases in glucocorticoids, exaggerated inflammatory responses, and increased pro-inflammatory gene expression in immune cells.
“Animals that sustain an injury during attack by the aggressor (Merlot et al., 2003) exhibit glucocorticoid resistant immune cells, systemic increases in glucocorticoids, exaggerated inflammatory responses (Avitsur et al., 2001; Stark et al., 2001), and increases in pro-inflammatory gene expression in immune cells (Powell et al., 2013).”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Stark et al., 2001
Glucocorticoid resistance occurs when immune cells become less sensitive to the anti-inflammatory effects of glucocorticoids due to persistent or repeated HPA axis activation.
“occurs when immune cells become less sensitive to the anti-inflammatory effects of glucocorticoids as a consequence of persistent or repeated activation of the HPA axis”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Stark et al, 2001
The immunosuppressive effect of GCs does not occur in splenocytes isolated from mice exposed to RSD.
“However, this immunosuppressive effect does not occur in splenocytes isolated from mice exposed to RSD (Stark et al, 2001).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Stark et al, 2001
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References 31 · Cited by 295
- Authors
- Stark, J. L., Avitsur, R., Padgett, D. A., Campbell, K. A., Beck, F. M., & Sheridan, J. F.
- Affiliations
- Neuroscience Graduate Studies Program, Sections of
- Oral Biology and
- The Ohio State University (US)
- Department of Molecular Virology, Immunology and Medical Genetics,
- Health Services Research,
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2001-06-01
- Volume
- 280
- Issue
- 6
- Pages
- R1799-R1805
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W1878109538
- Cited by
- 295
- References
- 31
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 8 · 2021: 14 · 2020: 9 · 2019: 12 · 2018: 11 · 2017: 16 · 2016: 16 · 2015: 14 · 2014: 15 · 2013: 13 · 2012: 19
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f31mh011792-01)
- National Institute of Mental Health (R01 MH46801-08, F31 MH11792, R01MH046801)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- social stress, glucocorticoid resistance, macrophages, corticosterone, splenocytes, interleukin-6, B cells, lipopolysaccharide, peripheral immune cells, psychosocial stress, splenomegaly
- MeSH terms
- Aggression, Animals, Cell Division, Corticosterone, Drug Resistance, Leukocyte Count, Leukocytes, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Reference Values, Social Environment, Spleen, Stress, Psychological, Interleukin-6, Mice
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