Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada.
Department of Psychiatry, University of Toronto, Toronto, ON M5T 2S8, Canada.
Cells. 2020 Apr 6;9(4):895. doi: 10.3390/cells9040895.
Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants ( = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ = 9.275, = 0.026), NF-κB (χ = 13.825, = 0.003), and inhibitor of NF-κB (IκBα) (χ = 7.990, = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ = 7.997, = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, = 0.029), but not placebo-treated, patients (r = 0.196, = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.
越来越多的证据表明神经炎症参与了双相情感障碍（BD）的发病机制。肿瘤坏死因子-α（TNF-α）拮抗剂英夫利昔单抗最近被报道可改善部分有 BD 病史和儿童期虐待史的患者的抑郁症状。为了探讨英夫利昔单抗作用的机制介质，我们研究了它与源自富含神经元来源的血浆细胞外囊泡（NEVs）的细胞对炎症反应的生物标志物的相互作用。我们假设与安慰剂相比，英夫利昔单抗会降低 TNF-α受体（TNFR）和核因子-κB（NF-κB）通路信号生物标志物，并且儿童期虐待史会调节英夫利昔单抗的作用。我们从这项临床试验的 55 名参与者的基线和第 2、6 和 12 周（终点）采集的血浆样本中免疫捕获了 NEVs，并使用免疫测定法测量了 NEV 生物标志物。一部分参与者（n = 27）还在基线和终点进行了全脑磁共振成像。童年期身体虐待调节了 TNFR1（χ=9.275，p=0.026）、NF-κB（χ=13.825，p=0.003）和 NF-κB 抑制剂（IκBα）α（χ=7.990，p=0.046）的治疗时间交互作用，表明身体虐待程度越高，随时间推移生物标志物的下降幅度越大。此外，英夫利昔单抗的抗抑郁反应受 TNFR1 调节（χ=7.997，p=0.046）。在英夫利昔单抗治疗的参与者中，TNFR1 水平的降低与抑郁症状的改善相关，而在安慰剂组中未检测到这种相关性。相反，在英夫利昔单抗治疗的患者中，TNFR1 水平的降低与皮质厚度的增加有关（r=-0.581，p=0.029），而在安慰剂治疗的患者中则没有相关性（r=0.196，p=0.501）。总之，我们报告说，NEVs 显示英夫利昔单抗以儿童期创伤依赖的方式与 BD 个体的 TNFR/NF-κB 神经炎症途径相互作用，这与临床反应和大脑结构变化有关。
