Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation.
Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation.
复制标题
Kynurenine途径代谢平衡会影响小胶质细胞活性：靶向Kynurenine单加氧酶降低神经炎症。
DOI：
10.1016/j.psyneuen.2018.04.019
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发表时间：
2018-08
影响因子：
3.7
通讯作者：
O'Connor JC
中科院分区：
文献类型：
--
作者：
Garrison AM;Parrott JM;Tuñon A;Delgado J;Redus L;O'Connor JC
慢性应激或炎症增加了犬尿氨酸途径(KP)上的色氨酸代谢，神经活性犬尿氨酸代谢物的产生有助于随后的抑郁样行为。小胶质细胞通过优先产生包括喹啉酸在内的氧化代谢产物来调节KP平衡。研究主要集中在细胞因子和HPA轴源性皮质类固醇在调节小胶质细胞活性中的相互作用，以及KP代谢物对神经元的直接影响；然而，KP代谢物直接对小胶质细胞活性的潜在作用尚不清楚。本实验用脂多糖(LPS)刺激小鼠小胶质细胞。6h后，IL-1β、IL-6、肿瘤坏死因子-α和诱导型一氧化氮合酶(INOS)的表达呈剂量依赖性增加，并伴随着氧化KP代谢限速酶吲哚-2，3-双加氧酶-1和犬尿氨酸-3-单加氧酶的表达。至24小时时，培养上清液中犬尿氨酸和喹啉酸含量升高。在内毒素刺激过程中，用Ro61-8048抑制KMO可减少细胞外亚硝酸盐的积累，减少KMO和肿瘤坏死因子-α的表达。同样，从KMO-/-小鼠分离的原代小胶质细胞对内毒素的促炎反应与WT对照组相比显著降低。为了确定KMO依赖代谢的底物(犬尿氨酸)或最终产物(喹啉酸)是否调节内毒素反应，用增加浓度的L犬尿氨酸或喹啉酸与脂多糖或生理盐水联合处理小胶质细胞。有趣的是，喹啉酸并没有影响小胶质细胞的内毒素反应。而L犬尿氨酸对内毒素反应有剂量依赖性抑制作用。这些数据首次显示了KMO抑制小胶质细胞在免疫攻击时的抗炎作用，并提示KP代谢平衡可能在调节小胶质细胞活性中起直接作用。
Chronic stress or inflammation increases tryptophan metabolism along the kynurenine pathway (KP), and the generation of neuroactive kynurenine metabolites contributes to subsequent depressive-like behaviors. Microglia regulate KP balance by preferentially producing oxidative metabolites, including quinolinic acid. Research has focused on the interplay between cytokines and HPA axis-derived corticosteroids in regulating microglial activity and effects of KP metabolites directly on neurons; however, the potential role that KP metabolites have directly on microglial activity is unknown. Here, murine microglia were stimulated with lipopolysaccharide(LPS). After 6 hours, mRNA expression of interleukin(IL)-1β, IL-6, tumor necrosis factor(TNF)-α and inducible nitric oxide synthase(iNOS) was dose-dependently increased along with the rate-limiting enzymes for oxidative KP metabolism, indoleamine-2,3-dioxygenase(IDO)-1 and kynurenine 3-monooxygenase(KMO). By 24 hours post-LPS, kynurenine and quinolinic acid in the media was elevated. Inhibiting KMO with Ro 61-8048 during LPS challenge attenuated extracellular nitrite accumulation and expression of KMO and TNF-α in response to LPS. Similarly, primary microglia isolated from KMO-/- mice exhibited a significantly reduced pro-inflammatory response to LPS compared to WT controls. To determine whether the substrate (kynurenine) or end product (quinolinic acid) of KMO-dependent metabolism modulates the LPS response, microglia were treated with increasing concentrations of L-kynurenine or quinolinic acid in combination with LPS or saline. Interestingly, quinolinic acid did not impact the microglial LPS response. However, L-kynurenine had dose-dependent inhibitory effect on the LPS response. These data are the first to show an anti-inflammatory effect of KMO inhibition on microglia during immune challenge and suggest that KP metabolic balance may play a direct role in regulating microglia activity.
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影响因子：
4.7
作者：
Parrott JM;O'Connor JC
通讯作者：
O'Connor JC
影响因子：
9.3
作者：
Lawson MA;Parrott JM;McCusker RH;Dantzer R;Kelley KW;O'Connor JC
通讯作者：
O'Connor JC
影响因子：
3.1
作者：
Clark, CJ;Mackay, GM;Phillips, RS
通讯作者：
Phillips, RS
影响因子：
3.3
作者：
CARPENEDO, R;CHIARUGI, A;MATTOLI, L
通讯作者：
MATTOLI, L
影响因子：
3.7
作者：
Frenois, Francois;Moreau, Maite;Castanon, Nathalie
通讯作者：
Castanon, Nathalie