Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, 300 UCLA Medical Plaza, Suite 3200A, Los Angeles, CA, 90095, USA.
Department of Psychology, University of California, Los Angeles, CA, USA.
Neuropsychopharmacology. 2019 Apr;44(5):923-929. doi: 10.1038/s41386-019-0316-9. Epub 2019 Jan 14.
Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18-50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P's < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory subtype of depression.
炎症在抑郁症的病理生理学中起着重要作用。然而，并非所有接触到炎症挑战的人都会发展成抑郁症，因此有必要确定哪些人有患病风险，以便制定有针对性的监测、预防和治疗策略。在一项随机、双盲、安慰剂对照研究（n=115）中，我们研究了白细胞转录组谱是否可以预测接受低剂量静脉内内毒素（n=58；年龄 18-50 岁）的志愿者中炎症引起的情绪低落。在基线时，使用外周血单核细胞的全基因组转录组谱和基于启动子的生物信息学分析评估转录因子（TF）的活性。然后，给参与者注射内毒素。使用心境状态问卷评估自我报告的情绪低落。基于将转录谱与抑郁障碍联系起来的现有研究，我们研究了基线时与免疫激活、交感神经激活和糖皮质激素不敏感相关的 TF 活性是否可以预测内毒素后情绪低落：核因子 kappa B（NF-kB）、cAMP 反应元件结合蛋白（CREB）和糖皮质激素受体（GR）。21 名参与者（36%）在接受内毒素后 2 小时内出现情绪低落，此时抑郁反应达到峰值。生物信息学分析控制年龄、性别、种族、体重指数和身体不适反应后，发现内毒素后情绪低落与与炎症相关的 TF（NF-kB）和β肾上腺素能信号相关的 TF（CREB）的基线活性增加以及与 GR 相关的 TF（NF-kB）的活性降低有关（P<0.001）。炎症引起的情绪低落可通过与免疫激活、交感神经激活和糖皮质激素不敏感相关的外周转录组谱来预测。通过进一步复制，这些与应激相关的分子谱可以用于识别具有炎症型抑郁症高危人群的新型基因组方法。
