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

Abstract

<jats:title>Abstract</jats:title><jats:p>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<jats:sub>50</jats:sub>-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<jats:sub>50</jats:sub>-Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC<jats:sub>50</jats:sub>-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.</jats:p>

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

“…Remaining ME values for modules M4-7 significantly increased with HCort treatment. Many terms within these modules enriched for immune processes such as positive regulation of isotype switching (P = 1.55 × 10 -3 ), regulation of NK T cell differentiation (P = 5.27 × 10 -5 ), and somatic recombination of immunoglobulin gene segments (P = 1.31 × 10 -3 ), processes that are well-established markers of glucocorticoid activation 8,9 . Finally, enrichments for hallmark glucocorticoid processes of histone acetylation 45 , such as H4 histone acetyltransferase activity (P = 3.77 × 10 -3 ) and transcriptional suppression (negative regulation of gene expression (P = 1.43 × 10 -3 )), were enriched.…”

“…Insights into the gene by environment (G×E) interactions underlying the psychiatric symptoms of PTSD remain poorly resolved, reflecting the lack of a cohesive neurobiological framework to investigate these mechanisms. To date, most studies of PTSD pathophysiology have focused on PBMCs, with PTSD patients showing lower ambient cortisol and heightened glucocorticoid sensitivity relative to healthy controls 6,7 coupled with increased expression of innate immune genes 8,9 . Toward resolving the relative contributions of genetic risk and environmental stress to PTSD pathophysiology, it is critical to deconvolve the impact of stress in a cell-specific manner, including determinants of stress responses across brain and blood cells.…”

GR‐α and GR‐β mRNA levels in peripheral blood mononuclear cells of acute myelitis patients can assist in the identification of glucocorticoid sensitivity and are correlated with glucocorticoid therapeutic effect

“…Possible prescription steroids for AM include intravenous corticosteroids methylprednisone or dexamethasone (Ali et al., 2019). Nevertheless, dysregulation of GR leads to GC tissue resistance, which contributes to enhanced inflammation (Somvanshi et al., 2020; Vassiliou et al., 2020). This study demonstrates that the GR‐α and GR‐β mRNA levels in PBMCs of AM patients can assist in the identification of GC sensitivity and are significantly correlated with GC efficacy.…”

Elevated Circulating Th2 Cells in Women With Asthma and Psychological Morbidity: A New Asthma Endotype?

“…43 Mechanistically, the influence of psychological stress on Th2-mediated inflammation and asthma is not well understood, though studies have shown durable changes in glucocorticoid receptor sensitivity and ensuing inflammation in patients with post-traumatic stress disorder. 44,45 On the other hand, the impact of earlylife psychological stress on asthma has also been reported to be associated with a hyporesponsive hypothalamic-pituitary-adrenal axis, independent of glucocorticoid receptor activity. 46 Further research is needed to fully delineate the mechanism(s) underlying stress-related asthma symptoms.…”