Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: Insights from a computational model for circadian-neuroendocrine-immune interactions

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 IC50-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 IC50-Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC50-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.

[1]  A. Menke,et al.  How to measure glucocorticoid receptor’s sensitivity in patients with stress-related psychiatric disorders , 2018, Psychoneuroendocrinology.

[2]  Hanspeter Herzel,et al.  Co-existing feedback loops generate tissue-specific circadian rhythms , 2018, Life Science Alliance.

[3]  Chad Hazlett,et al.  Covariate balancing propensity score for a continuous treatment: Application to the efficacy of political advertisements , 2018 .

[4]  Zhewu Wang,et al.  Posttraumatic Stress Disorder: An Immunological Disorder? , 2017, Front. Psychiatry.

[5]  Nicolas C. Nicolaides,et al.  Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes , 2017, Hormones.

[6]  John R. Terry,et al.  Dynamic responses of the adrenal steroidogenic regulatory network , 2017, Proceedings of the National Academy of Sciences.

[7]  M. Olufsen,et al.  Integrated Inflammatory Stress (ITIS) Model , 2017, Bulletin of mathematical biology.

[8]  A. Hoke,et al.  Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post-traumatic stress disorder , 2017, Translational Psychiatry.

[9]  S. Elsenbruch,et al.  Sex differences in the pro-inflammatory cytokine response to endotoxin unfold in vivo but not ex vivo in healthy humans , 2017, Innate immunity.

[10]  K. De Bosscher,et al.  Glucocorticoid receptors: finding the middle ground. , 2017, The Journal of clinical investigation.

[11]  R. Newton,et al.  Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance , 2017, The Journal of Biological Chemistry.

[12]  M. Foss,et al.  HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome , 2017, Diabetes/metabolism research and reviews.

[13]  Beatrijs Moerkerke,et al.  medflex : an R package for flexible mediation analysis using natural effect models , 2017 .

[14]  C. Weber,et al.  Neutrophils as protagonists and targets in chronic inflammation , 2017 .

[15]  O. Wolkowitz,et al.  Increased pro-inflammatory milieu in combat related PTSD – A new cohort replication study , 2017, Brain, Behavior, and Immunity.

[16]  Inmaculada Álvarez,et al.  A Panel Data Toolbox for MATLAB , 2017 .

[17]  Yuqing Wu,et al.  Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period , 2017, Journal of Neuroinflammation.

[18]  Rohit T. Rao,et al.  Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis. , 2016, American journal of physiology. Endocrinology and metabolism.

[19]  G. Neigh,et al.  Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment. , 2016, Current opinion in pharmacology.

[20]  T. VanderWeele.  Mediation Analysis: A Practitioner's Guide. , 2016, Annual review of public health.

[21]  Jennifer L. Hill,et al.  Assessing Sensitivity to Unmeasured Confounding Using a Simulated Potential Confounder , 2016 .

[22]  Guia Guffanti,et al.  An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress , 2015, Psychoneuroendocrinology.

[23]  Michael J. Meaney,et al.  Lower Methylation of Glucocorticoid Receptor Gene Promoter 1F in Peripheral Blood of Veterans with Posttraumatic Stress Disorder , 2015, Biological Psychiatry.

[24]  Nicole M. Taylor,et al.  Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress , 2014, Brain, Behavior, and Immunity.

[25]  J. Cidlowski,et al.  One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids , 2014, Neuroimmunomodulation.

[26]  G. Chrousos,et al.  Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor , 2014, BMC Endocrine Disorders.

[27]  Jing Xiao,et al.  The relationship between glucocorticoid receptor polymorphisms, stressful life events, social support, and post-traumatic stress disorder , 2014, BMC Psychiatry.

[28]  T. Elbert,et al.  Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors , 2014, The Journal of Neuroscience.

[29]  W. Bos,et al.  Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia. , 2014, British journal of clinical pharmacology.

[30]  G. Turecki,et al.  Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder , 2014, Translational Psychiatry.

[31]  T. Elbert,et al.  Reduced Peripheral Expression of the Glucocorticoid Receptor α Isoform in Individuals with Posttraumatic Stress Disorder: A Cumulative Effect of Trauma Burden , 2014, PloS one.

[32]  J. Veerman,et al.  Effective components of feedback from Routine Outcome Monitoring (ROM) in youth mental health care: study protocol of a three-arm parallel-group randomized controlled trial , 2014, BMC Psychiatry.

[33]  J. Cidlowski,et al.  The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. , 2013, The Journal of allergy and clinical immunology.

[34]  Kwang-Hyun Cho,et al.  Encyclopedia of Systems Biology , 2013, Springer New York.

[35]  G. Knežević,et al.  Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[36]  J. Rohwer,et al.  Impact of Glucocorticoid Receptor Density on Ligand-Independent Dimerization, Cooperative Ligand-Binding and Basal Priming of Transactivation: A Cell Culture Model , 2013, PloS one.

[37]  B. Oken,et al.  Salivary cortisol lower in posttraumatic stress disorder. , 2013, Journal of traumatic stress.

[38]  G. Fernández,et al.  Glucocorticoid receptor number predicts increase in amygdala activity after severe stress , 2012, Psychoneuroendocrinology.

[39]  Ellen Frank,et al.  Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk , 2012, Proceedings of the National Academy of Sciences.

[40]  Eric Vermetten,et al.  Glucocorticoid Receptor Pathway Components Predict Posttraumatic Stress Disorder Symptom Development: A Prospective Study , 2012, Biological Psychiatry.

[41]  Francis J. Doyle,et al.  Modeling Cortisol Dynamics in the Neuro-endocrine Axis Distinguishes Normal, Depression, and Post-traumatic Stress Disorder (PTSD) in Humans , 2012, PLoS Comput. Biol..

[42]  U. Fuhr,et al.  Pharmacokinetics, pharmacodynamics, and comparative bioavailability of single, oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized, controlled, crossover study in healthy adult volunteers. , 2011, Clinical therapeutics.

[43]  R. Yehuda,et al.  Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis. , 2011, Endocrinology.

[44]  K. Chapman,et al.  The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights , 2011, Molecular and Cellular Endocrinology.

[45]  D. Luckenbaugh,et al.  Sustained Elevation of Serum Interleukin-6 and Relative Insensitivity to Hydrocortisone Differentiates Posttraumatic Stress Disorder with and Without Depression , 2010, Biological Psychiatry.

[46]  O. Wolf,et al.  Lipopolysaccharide-induced experimental immune activation does not impair memory functions in humans , 2010, Neurobiology of Learning and Memory.

[47]  O. Wolf,et al.  Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder , 2010, Neuroscience & Biobehavioral Reviews.

[48]  C. Libert,et al.  Crosstalk between TNF and glucocorticoid receptor signaling pathways. , 2010, Cytokine & growth factor reviews.

[49]  S. Maier,et al.  Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide , 2010, Brain, Behavior, and Immunity.

[50]  E. Binder.  The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders , 2009, Psychoneuroendocrinology.

[51]  R. Yehuda.  Status of Glucocorticoid Alterations in Post‐traumatic Stress Disorder , 2009, Annals of the New York Academy of Sciences.

[52]  N. Simon,et al.  Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder , 2009, Depression and anxiety.

[53]  R. Yehuda,et al.  Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses. , 2008, The international journal of neuropsychopharmacology.

[54]  U. Schnyder,et al.  Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. , 2007, Journal of psychiatric research.

[55]  H. Westenberg,et al.  Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder , 2007, Molecular Psychiatry.

[56]  Dragan Dekaris,et al.  Circulating lymphocyte subsets, natural killer cell cytotoxicity, and components of hypothalamic-pituitary-adrenal axis in Croatian war veterans with posttraumatic stress disorder: cross-sectional study. , 2007, Croatian medical journal.

[57]  H. Westenberg,et al.  Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. , 2006, Journal of psychiatric research.

[58]  J. Kinzie,et al.  Cortisol production rate in posttraumatic stress disorder. , 2006, The Journal of clinical endocrinology and metabolism.

[59]  R. Yehuda,et al.  Advances in Understanding Neuroendocrine Alterations in PTSD and Their Therapeutic Implications , 2006, Annals of the New York Academy of Sciences.

[60]  Steve E. Calvano,et al.  Acute Inflammatory Response to Endotoxin in Mice and Humans , 2005, Clinical Diagnostic Laboratory Immunology.

[61]  E. Carlson,et al.  Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder , 2004, Biological Psychiatry.

[62]  C. Kirschbaum,et al.  Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder , 2004, Biological Psychiatry.

[63]  R. Yehuda,et al.  Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone. , 2003, Journal of psychiatric research.

[64]  T. Berki,et al.  Flow cytometric determination of glucocorticoid receptor (GCR) expression in lymphocyte subpopulations: lower quantity of GCR in patients with post‐traumatic stress disorder (PTSD) , 2003, Clinical and experimental immunology.

[65]  J. Cidlowski,et al.  Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform: A mechanism for the generation of glucocorticoid resistance , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  T. van der Poll,et al.  Proinflammatory Effects of IL-10 During Human Endotoxemia1 , 2000, The Journal of Immunology.

[67]  A. Dunn.  Cytokine Activation of the HPA Axis , 2000, Annals of the New York Academy of Sciences.

[68]  E. Young,et al.  Differential Regulation of Hippocampal Glucocorticoid Receptors mRNA and Fast Feedback: Relevance to Post‐Traumatic Stress Disorder , 1999, Journal of neuroendocrinology.

[69]  G. Chrousos,et al.  Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. , 1996, Endocrine reviews.

[70]  E. Giller,et al.  Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. , 1995, Archives of general psychiatry.

[71]  E. Giller,et al.  Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders , 1993, Biological Psychiatry.

[72]  S. Southwick,et al.  Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder. , 1991, The American journal of psychiatry.

[73]  J. Gustafsson,et al.  Down-regulation of glucocorticoid receptor mRNA by glucocorticoid hormones and recognition by the receptor of a specific binding sequence within a receptor cDNA clone. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Justin S. Hogg,et al.  Modeling and Hemofiltration Treatment of Acute Inflammation. , 2016, Processes.

[75]  E. Geuze,et al.  Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. , 2011, The American journal of psychiatry.

[76]  E. Graul,et al.  Dose-dependent pharmacokinetics of dexamethasone , 2004, European Journal of Clinical Pharmacology.

[77]  A. Turnbull,et al.  Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. , 1999, Physiological reviews.

[78]  R. Brattsand,et al.  Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. , 1996, Alimentary pharmacology & therapeutics.