Transcriptomic predictors of inflammation-induced depressed mood
Transcriptomic predictors of inflammation-induced depressed mood
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DOI：
10.1038/s41386-019-0316-9
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发表时间：
2019-04-01
影响因子：
7.6
通讯作者：
Cole, Steve W.
中科院分区：
文献类型：
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作者：
Cho, Joshua Hyong-Jin;Irwin, Michael R.;Cole, Steve W.
炎症在抑郁症的病理生理学中起着重要作用。然而，并非所有暴露于炎症挑战的个体都会发展为抑郁症，识别那些有风险的人对于制定有针对性的监测，预防和治疗策略是必要的。在一项随机双盲安慰剂对照研究（n = 115）中，我们检查了白细胞转录组谱是否预测了接受低剂量静脉内毒素的志愿者（n = 58;年龄18-50）中炎症诱导的抑郁情绪。在基线时，使用外周血单核细胞的全基因组转录谱和基于启动子的生物信息学分析评估转录因子（TF）活性。然后，参与者被给予内毒素。自我报告的抑郁情绪进行了评估，使用情绪状态的轮廓。基于将转录谱与抑郁障碍联系起来的现有研究，我们检测了是否可通过与免疫激活、交感神经激活和糖皮质激素不敏感性相关的转录因子的基线活性预测内毒素后抑郁情绪：分别为核因子κ B（NF-κ B）、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%）的抑郁情绪从基线到内毒素后2小时（抑郁反应达到峰值）有所增加。控制年龄、性别、种族、体重指数和身体疾病反应的生物信息学分析显示，内毒素后抑郁情绪可通过与炎症相关的TF（NF-κ B）和β-肾上腺素能信号传导（CREB）的基线活性增加以及GR相关的TF活性降低来预测（P < 0.001）。通过与免疫激活、交感神经激活和糖皮质激素不敏感性相关的外周转录组谱预测炎症诱导的抑郁情绪。通过进一步的复制，这些与压力相关的分子谱可以用于一种新的基因组方法，用于识别抑郁症炎症亚型的高风险个体。
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. Selfreported 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.