Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing PPP, TCA cycle, and OXPHOS, to aid in the phenotypic transition towards alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation towards pro-resolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h post LPS stimulation that included succinate dehydrogenase complex (Sdh), pyruvate kinase (Pkm), and sedoheptulosekinase (Shpk). Se-dependent modulation of these pathways predisposed BMDMs to preferentially increase OXPHOS to efficiently regulate inflammation and its timely resolution. Use of macrophages lacking selenoproteins, indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of Sdh with dimethylmalonate affected the pro-resolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and pro-resolution.

中文翻译：

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炎症和消退过程中硒依赖的代谢重编程

微量元素硒（Se）作为第21个氨基酸硒半胱氨酸（Sec）通过tRNA [Ser] Sec掺入硒蛋白中。硒蛋白充当氧化还原稳态的守门员，并调节免疫功能以实现抗炎和消退。然而，关于炎症和消退过程中代谢重新编程的机制基础仍然知之甚少。在有或没有硒（亚硒酸盐）的条件下培养的小鼠骨髓源巨噬细胞（BMDM）的细菌内毒素脂多糖（LPS）活化作用，通过多重串联质量标签定量蛋白质组学，代谢组学研究了蛋白质组和代谢组的时间变化，以及机器学习方法。动力学deltagram和聚类分析表明，添加Se导致LPS刺激PPP，TCA周期和OXPHOS刺激后，细胞代谢发生大量重编程，以帮助表型向交替激活的巨噬细胞过渡，这与炎症消退同义。硒在0 h开始进行代谢途径重塑，随后代谢适应前表型，LPS刺激后8h左右最为突出，包括琥珀酸脱氢酶复合物（Sdh），丙酮酸激酶（Pkm）和sedoheptulosekinase（Shpk）。 。这些途径的硒依赖性调节使BMDMs优先增加OXPHOS以有效调节炎症及其及时解决。使用缺乏硒蛋白的巨噬细胞，表明所有三个代谢节点都对硒蛋白表达敏感。此外，丙二酸二甲酯对Sdh的抑制作用通过增加鼠腹膜炎模型的分离间隔来影响Se的促分辨作用。总而言之，我们的研究通过代谢重编程以促进抗发炎和促进分解，从而为细胞硒的作用提供了新颖的见解。