Indoleamine 2,3-dioxygenase 1 (IDO1) is the first rate-limiting enzyme that metabolizes tryptophan to the kynurenine pathway. Its activity is highly inducible by pro-inflammatory cytokines and correlates with the severity of major depressive disorder (MDD). MicroRNAs (miRNAs) are involved in gene regulation and the development of neuropsychiatric disorders including MDD. However, the role of miRNAs in targeting IDO1 in the pathophysiology of MDD is still unknown. In this study, we investigated the role of novel miRNAs in the regulation of IDO1 activity and its effect on lipopolysaccharide (LPS)-induced depression-like behavior in mice. LPS up-regulated miR-874-3p concomitantly with increase in IDO1 expression in the prefrontal cortex (PFC), increase in immobility in the forced swimming test as depression-like behavior and decrease in locomotor activity as sickness behavior without motor dysfunction. The miR-874-3p increased in both neuron and microglia after LPS. Its mimic significantly suppressed LPS-induced IDO1 expression in the PFC. Infusion of IDO1 inhibitor (1-methyl-l-tryptophan) and miR-874-3p into PFC prevented an increase in immobility in the forced swimming test, but did not decrease in locomotor activity induced by LPS. These results suggest that miR-874-3p may play an important role in preventing the LPS-induced depression-like behavior through inhibition of IDO1 expression. This may also serve as a novel potential target molecule for the treatment of MDD.

中文翻译：

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前额叶皮层 miR-874-3p 通过抑制小鼠吲哚胺 2,3-双加氧酶 1 的表达来防止脂多糖诱导的抑郁样行为

吲哚胺 2,3-双加氧酶 1 (IDO1) 是第一种将色氨酸代谢为犬尿氨酸途径的限速酶。它的活性是由促炎细胞因子高度诱​​导的，并且与重度抑郁症 (MDD) 的严重程度相关。MicroRNAs (miRNAs) 参与基因调控和包括 MDD 在内的神经精神疾病的发展。然而，miRNA在MDD病理生理学中靶向IDO1的作用尚不清楚。在这项研究中，我们研究了新型 miRNA 在调节 IDO1 活性中的作用及其对脂多糖 (LPS) 诱导的小鼠抑郁样行为的影响。LPS 上调 miR-874-3p 伴随着前额叶皮层 (PFC) 中 IDO1 表达的增加，强迫游泳试验中不动增加表现为抑郁样行为，运动活动减少表现为无运动功能障碍的病态行为。LPS后神经元和小胶质细胞中的miR-874-3p均增加。它的模拟物显着抑制了 PFC 中 LPS 诱导的 IDO1 表达。IDO1抑制剂（1-甲基-l-色氨酸）和 miR-874-3p 进入 PFC 阻止了强迫游泳测试中不动性的增加，但不会降低 LPS 诱导的运动活性。这些结果表明 miR-874-3p 可能通过抑制 IDO1 表达在预防 LPS 诱导的抑郁样行为中发挥重要作用。这也可以作为治疗 MDD 的新型潜在靶分子。