The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, Scotland, UK.
School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln, Lincolnshire, UK.
J Leukoc Biol. 2018 Apr;103(4):681-692. doi: 10.1002/JLB.3A0617-261R. Epub 2018 Jan 26.
Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.
有几条证据表明，巨噬细胞激活和炎症与抑郁症的病因中的（单胺能）神经系统有关。IFN 治疗与抑郁症状相关，而抗 TNF-α 疗法则引起积极的情绪。本研究描述了 2 种单胺能抗抑郁药（依他普仑、去甲替林）和 3 种抗炎药（吲哚美辛、泼尼松龙和抗 TNF-α 抗体）对来自 6 个人的人单核细胞衍生的巨噬细胞（MDM）对 LPS 或 IFN-α 反应的作用。表达谱分析显示，LPS 刺激后 MDM 转录组发生了强烈变化（P<0.001 时有 3294 个基因），而 IFNα 只引起了更有限的一组基因（499 个）的反应。与已发表的报告相反，在非毒性剂量下，两种单胺能抗抑郁药均未显著调节对任一炎症挑战的转录反应。每种抗炎药对炎症细胞因子的表达和诱导基因表达谱都有独特的影响——特别是对参与色氨酸代谢的酶的调节。除其他外，抗 TNF-α 抗体的作用证实了人类巨噬细胞中存在一个预测的自分泌刺激环。转录变化可预测色氨酸的可用性和犬尿氨酸的合成，通过对细胞上清液进行靶向代谢组学研究进行分析。我们认为，大脑或外周的炎症过程可能通过改变色氨酸用于 5-羟色胺合成的可用性或通过增加神经毒性犬尿氨酸的产生来影响抑郁症。
