Increased mitochondrial arginine metabolism supports bioenergetics in asthma
Increased mitochondrial arginine metabolism supports bioenergetics in asthma
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DOI：
10.1172/jci82925
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Erzurum, Serpil C.
中科院分区：
文献类型：
--
作者：
Xu, Weiling;Ghosh, Sudakshina;Erzurum, Serpil C.
高水平的精氨酸代谢酶，包括诱导型一氧化氮合酶（iNOS）和精氨酸酶（ARG），是典型的哮喘气道上皮细胞;然而，鲜为人知的是，在哮喘中的精氨酸流量增加的代谢作用。在这里，我们证明了代谢增加维持精氨酸在哮喘气道上皮细胞的生物能量学和炎症的后果。与健康对照组相比，哮喘肺样本中iNOS、ARG 2、精氨酸合成酶和线粒体呼吸复合物III和IV的表达升高。ARG 2在人支气管上皮细胞系中的过表达加速了氧化生物能途径，抑制了低氧诱导因子（HIF）和特应性Th 2炎症状态（pSTAT 6）信号转导子的磷酸化，这两者都与哮喘病因有关。Arg 2缺陷小鼠的线粒体更少！膜电位和更大的HIF-2 α比WT动物。在过敏原诱导的哮喘模型中，缺乏Arg 2的小鼠比WT小鼠具有更大的Th 2炎症，如通过更高水平的pSTAT 6、IL-13、IL-17、嗜酸性粒细胞活化趋化因子和嗜酸性粒细胞以及更多的粘液化生所指示的。Arg 2缺陷小鼠的骨髓移植不影响受体小鼠的气道炎症，支持常驻肺细胞作为Th 2炎症升高的驱动因素。这些数据表明，精氨酸流量保持细胞呼吸和抑制病理信号事件，促进哮喘炎症。
High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxiainducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STATE (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondria! membrane potential and greater HIF-2 alpha than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.