In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior. Duration of depression-like behavior was markedly prolonged in mice without mature T or B lymphocytes (Rag1^-/- mice). This prolonged depression-like behavior was associated with persistent upregulation of the tryptophan-metabolizing enzyme indoleamine-2,3-dioxygenase (Ido)1 in the prefrontal cortex (PFC). Reconstitution of Rag1^-/- mice with T lymphocytes normalized resolution of depression-like behavior and expression of Ido1 in the PFC. During resolution of inflammation-induced depression-like behavior, T lymphocytes accumulated in the meninges and were required for induction of interleukin (IL)-10 in the meninges and the PFC. Inhibition of IL-10 signaling by nasal administration of neutralizing anti-IL-10 antibody to WT mice led to persistent upregulation of Ido1 in the PFC and prolonged depression-like behavior. Conversely, nasal administration of recombinant IL-10 in Rag1^-/- mice normalized Ido1 expression and resolution of depression-like behavior. In conclusion, the present data show for the first time that resolution of inflammation-induced depression is an active process requiring T lymphocytes acting via an IL-10-dependent pathway to decrease Ido1 expression in the brain. We propose that targeting the T lymphocyte/IL-10 resolution pathway could represent a novel approach to promote recovery from major depressive disorder.

中文翻译：

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解决炎症引起的抑郁症需要T淋巴细胞和内源性脑白介素10信号传导。

在人类中，抑郁症通常与低度炎症，色氨酸/犬尿氨酸途径的激活以及轻度淋巴细胞减少有关。临床前研究证实，炎症通过色氨酸/犬尿氨酸途径的激活而诱发抑郁症样的行为。然而，控制从抑郁中恢复的机制尚不清楚。了解导致抑郁症消退的途径可能会导致确定新的治疗目标。我们调查了T淋巴细胞对脂多糖诱导的抑郁样行为的解决的贡献。在没有成熟的T或B淋巴细胞的小鼠中，抑郁样行为的持续时间显着延长（Rag1 ^-/-老鼠）。这种长时间的抑郁样行为与前额叶皮层（PFC）中色氨酸代谢酶吲哚胺-2,3-双加氧酶（Ido）1的持续上调有关。用T淋巴细胞重建Rag1 ^-/-小鼠可使PFC中抑郁样行为和Ido1表达的分辨率正常化。在炎症引起的抑郁样行为的消退过程中，T淋巴细胞在脑膜中积聚，是诱导脑膜和PFC中白介素（IL）-10所必需的。通过向野生型小鼠经鼻中和抗IL-10抗体对IL-10信号的抑制，导致PFC中Ido1的持续上调并延长了抑郁症的行为。相反，在鼻腔给药Rag1中重组IL-10 ^-/-小鼠使Ido1表达正常化，并消除了抑郁症样行为。总之，本数据首次表明，炎症诱导的抑郁症的解决是一个活跃的过程，需要T淋巴细胞通过依赖IL-10的途径起作用来降低脑中Ido1的表达。我们建议针对T淋巴细胞/ IL-10的解决途径可能代表一种新型的方法来促进从重度抑郁症的恢复。