Biobehavioral Role of Brain Kynurenine Metabolism in Mental Illness

描述(申请人提供)：促炎细胞因子在大脑中起作用，调节对身心健康至关重要的重要生物行为过程。接受细胞因子免疫治疗以治疗病毒感染或恶性肿瘤的患者以及患有慢性炎症性疾病的患者患抑郁症的风险增加。这些免疫-大脑相互作用背后的神经生物学机制和免疫底物仍不清楚。实验室啮齿动物外周天然免疫系统的急性和慢性激活导致了抑郁样的生物行为。我们实验室的新数据表明，这些生物行为是由细胞因子诱导的色氨酸降解酶吲哚-2，3-双加氧酶(IDO)的激活所介导的，IDO是犬尿氨酸途径的第一个限速酶。我们证明，药物抑制或IDO的基因缺失可以防止外周免疫激活后抑郁样的生物行为。我们最新的数据表明，大脑中神经活性犬尿氨酸代谢物的产生可能是抑郁样生物行为增加的神经生物学机制。临床上，在接受细胞因子免疫治疗的患者中，循环色氨酸减少和犬尿氨酸浓度(IDO活性的第一个分解代谢产物)增加与抑郁评分增加相关。我们的新数据扩展了这些临床观察，表明免疫应激小鼠的抑郁样行为需要细胞因子诱导的IDO活性。事实上，直接给药犬尿氨酸会在幼鼠中诱导抑郁样行为，但犬尿氨酸并不具有神经活性。取而代之的是，犬尿氨酸在大脑中隔室代谢，产生产生自由基或谷氨酸活性的犬尿氨酸代谢物。小胶质细胞产生自由基代谢产物3-羟基犬尿氨酸和3-羟基邻氨基苯甲酸，从而产生离子亲性谷氨酸受体激动剂喹啉酸。相反，内皮细胞和星形胶质细胞产生犬尿酸，这是一种谷氨酸和17-烟碱型乙酰胆碱受体拮抗剂。基于这些数据，我们假设激活的小胶质细胞中的犬尿氨酸代谢驱动炎症诱导的抑郁样生物行为的发展。我们将首先确定小胶质细胞的激活是否对外周免疫应激后依赖IDO的抑郁样行为负责。目标二将确定外周免疫激活与脑犬尿氨酸代谢变化之间的调节途径，目标三将利用体外和体外技术明确犬尿氨酸代谢是如何在细胞水平上调节的。最后一个目标将使用药理学和遗传学方法来靶向犬尿氨酸途径酶，这些酶可能会减轻细胞因子诱导的抑郁样生物行为。这些临床前实验需要了解促炎细胞因子引起精神病理学的神经生物学机制，并确定治疗炎症性抑郁症的新靶点。 与公共卫生相关：抑郁症是慢性身体疾病和感染的最常见、最虚弱和代价最高的共病之一。不幸的是，调节这些神经免疫相互作用的分子和细胞机制仍不清楚。我们最近发现了一种代谢途径(犬尿氨酸途径)，它在大脑中上调，以响应外周天然免疫系统的激活。看来，在外周免疫激活后，脑支持细胞小胶质细胞产生神经活性犬尿氨酸代谢产物，导致小鼠抑郁行为的发生。成功地解开这些分子网络将使开发新的治疗策略来治疗炎症诱导的抑郁症。

DESCRIPTION (provided by applicant): Proinflammatory cytokines act in the brain to regulate important biobehavioral processes that are critical for physical and mental health. Patients receiving cytokine immunotherapy for treatment of viral infections or malignancies and those suffering from chronic inflammatory diseases are at an increased risk of developing depressive disorders. The neurobiological mechanisms and immune substrates underlying these immune-brain interactions remain unclear. Acute and chronic activation of the peripheral innate immune system in laboratory rodents precipitates depressive-like biobehaviors. New data from our laboratory have demonstrated that these biobehaviors are mediated by cytokine-induced activation of the tryptophan-degrading enzyme indoleamine 2, 3 dioxygenase (IDO), which is the first and rate-limiting enzyme of the kynurenine pathway. We demonstrated that pharmacologic inhibition or genetic deletion of IDO prevents depressive-like biobehaviors following peripheral immune activation. Our most recent data point to the generation of neuroactive kynurenine metabolites in the brain as the likely neurobiological mechanism for increased depressive-like biobehaviors. Clinically, reduced circulating tryptophan and increased kynurenine concentrations (the first catabolic product of IDO activity) are correlated with increased depression scores in patients undergoing cytokine immunotherapy. Our new data extend these clinical observations to show that depressive-like behavior in immune-stressed mice requires cytokine-induced IDO activity. In fact, direct administration of kynurenine induces depressive-like behavior in naive mice, but kynurenine is not neuroactive. Instead, kynurenine is compartmentally metabolized in the brain to generate free radical-producing or glutamatergically-active kynurenine metabolites. Microglia produce the free radical forming metabolites 3-hydroxykynurenine and 3-hydroxyanthranilic acid en route to generating the ionotropic glutamate receptor agonist, quinolinic acid. Conversely, endothelial cells and astrocytes produce kynurenic acid, which is a glutamate and 17-nicotinic acetylcholine receptor antagonist. Based on these data, we hypothesize that kynurenine metabolism in activated microglia drives development of inflammation-induced depressive-like biobehaviors. We will first determine if microglial activation is responsible for IDO-dependent depressive-like behavior following peripheral immune stress. Objective two will define the regulatory pathways that link peripheral immune activation to changes in brain kynurenine metabolism, and objective three will utilize ex vivo and in vitro techniques to specifically define how kynurenine metabolism is regulated at the cellular level. The last objective will use pharmacologic and genetic approaches to target kynurenine pathway enzymes that might alleviate cytokine-induced depressive-like biobehaviors. These preclinical experiments are needed to understand the neurobiological mechanisms by which proinflammatory cytokines cause psychopathology and to identify novel therapeutic targets for the treatment of inflammation-induced depression. PUBLIC HEALTH RELEVANCE: Depression represents one of the most frequent, debilitating and costly comorbidities of chronic physical illness and infection. Unfortunately, the molecular and cellular mechanisms that mediate these neuro-immune interactions remain unclear. We have recently identified a metabolic pathway (the kynurenine pathway) that is upregulated in the brain in response to activation of the peripheral innate immune system. It appears that the generation of neuroactive kynurenine metabolites by brain support cells called microglia, following peripheral immune activation, is responsible for precipitating depressive behaviors in mice. Successfully unraveling these molecular networks will enable the development of novel therapeutic strategies to treat inflammation-induced depression.