Species-Specific Transcriptional Regulation of Genes Involved in Nitric Oxide Production and Arginine Metabolism in Macrophages.
Species-Specific Transcriptional Regulation of Genes Involved in Nitric Oxide Production and Arginine Metabolism in Macrophages.
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DOI：
10.4049/immunohorizons.1700073
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Hume DA
中科院分区：
文献类型：
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作者：
Young R;Bush SJ;Lefevre L;McCulloch MEB;Lisowski ZM;Muriuki C;Waddell LA;Sauter KA;Pridans C;Clark EL;Hume DA
激活的小鼠巨噬细胞通过NO合成酶（NOS2）代谢精氨酸产生NO作为抗菌效应物。已发表的基因表达数据集很少支持在人巨噬细胞中激活这一途径。NO的产生需要多个基因的协同调控。我们从具有代表性的啮齿动物（大鼠）、单胃动物（猪和马）和反刍动物（绵羊、山羊、牛和水牛）的骨髓来源的巨噬细胞中获得了rna测序数据，并分析了在LPS刺激下参与精氨酸代谢的基因表达。在大鼠中，和小鼠一样，LPS强烈诱导Nos2、精氨酸转运体Slc7a2、精氨酸酶1 （Arg1）、GTP环水解酶（Gch1）和精氨酸琥珀酸合成酶（Ass1）。这些反应在物种间都不保守。只有牛和水牛表现出明显的NOS2诱导。所研究的物种在精氨酸酶（ARG2，而不是ARG1）和氨基酸转运蛋白的表达和调控方面也存在差异。物种间的变异与启动子的快速进化有关。反刍动物物种间NOS2和ARG2的诱导差异与Bov-A2反转录转座子在启动子区域的插入有关。Bov-A2在转染RAW264.7巨噬细胞中具有lps诱导的增强子活性。与先天免疫功能一致，物种间NO的产生和精氨酸代谢差异很大，这种差异可能有助于病原体宿主的限制。
Activated mouse macrophages metabolize arginine via NO synthase (NOS2) to produce NO as an antimicrobial effector. Published gene expression datasets provide little support for the activation of this pathway in human macrophages. Generation of NO requires the coordinated regulation of multiple genes. We have generated RNA-sequencing data from bone marrow–derived macrophages from representative rodent (rat), monogastric (pig and horse), and ruminant (sheep, goat, cattle, and water buffalo) species, and analyzed the expression of genes involved in arginine metabolism in response to stimulation with LPS. In rats, as in mice, LPS strongly induced Nos2, the arginine transporter Slc7a2, arginase 1 (Arg1), GTP cyclohydrolase (Gch1), and argininosuccinate synthase (Ass1). None of these responses was conserved across species. Only cattle and water buffalo showed substantial NOS2 induction. The species studied also differed in expression and regulation of arginase (ARG2, rather than ARG1), and amino acid transporters. Variation between species was associated with rapid promoter evolution. Differential induction of NOS2 and ARG2 between the ruminant species was associated with insertions of the Bov-A2 retrotransposon in the promoter region. Bov-A2 was shown to possess LPS-inducible enhancer activity in transfected RAW264.7 macrophages. Consistent with a function in innate immunity, NO production and arginine metabolism vary greatly between species and differences may contribute to pathogen host restriction.