Harvard John Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, California.
Am J Physiol Endocrinol Metab. 2020 Jul 1;319(1):E48-E66. doi: 10.1152/ajpendo.00398.2019. Epub 2020 Apr 21.
Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (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 (DEX) suppression test and IC-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 proinflammatory response. The adaptive response of proinflammatory 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 neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F (), IC, and proinflammatory cytokines. We noted significant mediation effects of 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.
尽管糖皮质激素抵抗会导致炎症增加，但创伤后应激障碍（PTSD）患者的糖皮质激素受体（GR）敏感性增加，同时炎症也增加。目前尚不清楚炎症如何与高反应性下丘脑-垂体-肾上腺（HPA）轴共存。为了更好地理解这一点，我们开发并分析了 HPA 轴和免疫系统的综合数学模型。我们通过改变模型参数，对地塞米松（DEX）抑制试验和 IC-地塞米松抑制细胞因子进行了数学模拟。模型分析表明，增加 GR 活性的剂量反应曲线的陡度可能会降低 GR 在环境糖皮质激素水平下的抗炎作用，从而增加促炎反应。由于 GR 介导的对 HPA 轴的负反馈对 HPA 轴的主导作用，促炎细胞因子介导的刺激对 HPA 轴的适应性反应降低。为了验证这些假设，我们分析了来自 PTSD 患者和非 PTSD 患者的战区退伍军人的神经内分泌变量和细胞因子的临床数据。我们观察到皮质醇和 ACTH 抑制试验、促炎细胞因子 TNFα 和 IL6、高敏 C 反应蛋白、GR 基因启动子甲基化以及溶菌酶抑制 IC 等方面存在显著的组间差异。因果推理模型揭示了皮质醇抑制与 DEX 后皮质醇下降、人类 GR 基因外显子 1F（）启动子甲基化、IC 和促炎细胞因子之间存在显著关联。我们注意到，启动子甲基化对通过 GR 敏感性变化引起的炎症细胞因子有显著的中介作用。我们的研究结果表明，GR 敏感性增加可能导致炎症增加；因此，恢复 GR 敏感性的干预措施可能会使 PTSD 中的炎症正常化。
