Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: insights from computational model for circadian-neuroendocrine-immune interactions
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Abstract
Abstract Although glucocorticoid resistance contributes to increased inflammation, individuals with post-traumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation co-exists with a hyper-responsive hypothalamic pituitary adrenal axis (HPA axis). To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone suppression test and IC 50 -dexamethasone for cytokine suppression, by varying model parameters. The model analysis suggests that increasing the steepness of the dose response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels thereby increasing pro-inflammatory response. The adaptive response of pro-inflammatory cytokine mediated stimulatory effects on the HPA-axis is reduced due to dominance of the GR-mediated negative feedback on the HPA-axis. To verify these hypotheses we analyzed the clinical data on neuro-endocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, pro-inflammatory cytokines TNFα and IL6, hs-CRP, promoter methylation of GR gene and IC 50 -Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC 50 -Dex and pro-inflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation, therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.
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The Hill function fits stimulus-response data in a wide set of biological systems.
“This agrees with general evidence that the Hill function fits stimulus-response data in a wide set of biological systems [123–128].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [128]
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Somvanshi, P. R., Mellon, S. H., Flory, J. D., Abu-Amara, D., PTSD Systems Biology Consortium;, Wolkowitz, O. M., Yehuda, R., Jett, M., Hood, L., Marmar, C., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00065.2019 · Cited by 40 · see citing works
Self-citationFibromyalgia pathogenesis explained by a neuroendocrine multistable model
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- Authors
- Somvanshi, P. R., Mellon, S. H., Yehuda, R., Flory, J. D., Makotkine, I., Bierer, L., Marmar, C., Jett, M., & Doyle, F. J.
- Affiliations
- Harvard University (US)
- University of California, San Francisco (US)
- James J. Peters VA Medical Center (US)
- Department of Psychiatry, New York Langone Medical School, New York, New York
- United States Army Medical Research and Development Command (US)
- Corresponding author
- Doyle, Francis J.
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2020-07-01
- Volume
- 319
- Issue
- 1
- Pages
- E48-E66
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W3016401445
- Cited by
- 55
- References
- 23
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 13 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 3 · 2019: 1
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- U S Army Medical Research and Material Command (W911NF-17-2-0086)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- post-traumatic stress disorder, glucocorticoid receptor sensitivity, glucocorticoid resistance, inflammation, hypothalamic-pituitary-adrenal axis, mathematical model, dexamethasone suppression test, inflammatory cytokines, TNF-α, interleukin-6, C-reactive protein, cortisol, ACTH, war veterans, causal inference
- MeSH terms
- Adrenocorticotropic Hormone, Adult, C-Reactive Protein, Circadian Rhythm, Dexamethasone, Glucocorticoids, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Inflammation, Male, Models, Theoretical, Pituitary-Adrenal Function Tests, Pituitary-Adrenal System, Promoter Regions, Genetic, Receptors, Glucocorticoid, Stress Disorders, Post-Traumatic, Tumor Necrosis Factor-alpha, Veterans, Interleukin-6, Case-Control Studies, Cytokines, DNA Methylation, Inhibitory Concentration 50, Iraq War, 2003-2011, Afghan Campaign 2001-
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