Parrott Jennifer M, Redus Laney, O'Connor Jason C
Department of Pharmacology, School of Medicine, Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 422D Medical Building MC-7764, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, 418D Medical Building MC-7764, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
J Neuroinflammation. 2016 May 27;13(1):124. doi: 10.1186/s12974-016-0590-y.
Inflammation increases the risk of developing depression-related symptoms, and tryptophan metabolism is an important mediator of these behavior changes. Peripheral immune activation results in central up-regulation of pro-inflammatory cytokine expression, microglia activation, and the production of neurotoxic kynurenine metabolites. The neuroinflammatory and kynurenine metabolic response to peripheral immune activation has been largely characterized at the whole brain level. It is unknown if this metabolic response exhibits regional specificity even though the unique indoleamine 2,3-dioxygenase (IDO)-dependent depressive-like behaviors are known to be controlled by discrete brain regions. Therefore, regional characterization of neuroinflammation and kynurenine metabolism might allow for better understanding of the potential mechanisms that mediate inflammation-associated behavior changes.
Following peripheral immune challenge with lipopolysaccharide (LPS), brain tissue from behaviorally relevant regions was analyzed for changes in mRNA of neuroinflammatory targets and kynurenine pathway enzymes. The metabolic balance of the kynurenine pathway was also determined in the peripheral circulation and these brain regions.
Peripheral LPS treatment resulted in region-independent up-regulation of brain expression of pro-inflammatory cytokines and glial cellular markers indicative of a neuroinflammatory response. The expression of kynurenine pathway enzymes was also largely region-independent. While the kynurenine/tryptophan ratio was elevated significantly in both the plasma and in each brain regions evaluated, the balance of kynurenine metabolism was skewed toward production of neurotoxic metabolites in the hippocampus.
The upstream neuroinflammatory processes, such as pro-inflammatory cytokine production, glial cell activation, and kynurenine production, may be similar throughout the brain. However, it appears that the balance of downstream kynurenine metabolism is a tightly regulated brain region-dependent process.
炎症会增加出现抑郁相关症状的风险，而色氨酸代谢是这些行为变化的重要调节因子。外周免疫激活导致促炎细胞因子表达在中枢上调、小胶质细胞激活以及神经毒性犬尿氨酸代谢产物的产生。外周免疫激活后的神经炎症和犬尿氨酸代谢反应在全脑水平上已得到很大程度的表征。尽管已知独特的吲哚胺2,3-双加氧酶（IDO）依赖性抑郁样行为受离散脑区控制，但尚不清楚这种代谢反应是否具有区域特异性。因此，对神经炎症和犬尿氨酸代谢进行区域表征可能有助于更好地理解介导炎症相关行为变化的潜在机制。
在用脂多糖（LPS）进行外周免疫刺激后，分析行为相关区域的脑组织中神经炎症靶点和犬尿氨酸途径酶的mRNA变化。还测定了外周循环和这些脑区中犬尿氨酸途径的代谢平衡。
外周LPS处理导致促炎细胞因子和指示神经炎症反应的胶质细胞标志物在脑内的表达出现不依赖区域的上调。犬尿氨酸途径酶的表达在很大程度上也不依赖区域。虽然血浆和每个评估脑区中的犬尿氨酸/色氨酸比值均显著升高，但犬尿氨酸代谢平衡在海马体中倾向于产生神经毒性代谢产物。
上游神经炎症过程，如促炎细胞因子产生、胶质细胞激活和犬尿氨酸产生，在整个大脑中可能相似。然而，下游犬尿氨酸代谢的平衡似乎是一个严格受调控的、依赖脑区的过程。
