Cellular Selenium Status and PGJ2 Metabolism (PA-17-078 supplement 2017)

描述（由申请人提供）：了解硒蛋白（含硒（Se）作为硒代半胱氨酸）的促分解功能的分子机制可能是缓解胃肠道（GI）损伤常见疾病的关键。使用三种不同的肠道损伤模型，例如葡聚糖硫酸钠（DSS）诱导的化学损伤，肠道致病性细菌、啮齿类柠檬酸杆菌或巴西日本圆线虫引起的GI感染，将检查肠道免疫系统解决炎症的能力。最后一个周期的研究表明，Se能够有效地将类花生酸代谢的花生四烯酸途径从巨噬细胞中的促炎前列腺素E2（PGE 2）分流到抗炎15-脱氧-Δ 12，14-PGJ 2（15 d-PGJ 2）。这种代谢物“类别转换”是氧化还原变化的结果，通过硒蛋白依赖性的转录因子、核因子（NF）-κB和过氧化物酶体增殖物激活受体（PPAR）-γ的差异调节，影响许多代谢途径，包括类花生酸和L-精氨酸（L-Arg）途径。因此，硒蛋白的表达是至关重要的极化促炎性M1（Th 1;经典激活）巨噬细胞向M2样（Th 2;交替激活）表型。我们的研究表明，代谢组的变化是这种表型向修复性M2巨噬细胞转变的关键，M2巨噬细胞具有抗炎和促消退特性，将在三种不同的模型中进行测试。初步数据表明，硒蛋白是至关重要的，有效地解决所有三种模型中的损伤。因此，我们的研究是基于总体假设，即硒蛋白表达改变代谢途径以减轻炎症，同时促进损伤后的消退。将使用巨噬细胞和T细胞中缺乏硒蛋白的小鼠来测试该假设：1）确定硒蛋白对化学损伤后M2巨噬细胞的促分解功能的作用; 2）确定硒蛋白在Th 2介导的感染后的炎症分解中的作用;以及3）确定硒蛋白在Th 1/Th 17介导的感染后的促分解功能。这些研究将测试硒蛋白的促分解特性是否依赖于三种胃肠道炎症模型中代谢组的变化。我们研究的长期目标是了解硒在GI稳态中的作用是通过免疫细胞代谢的变化介导的。

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that underlie the pro-resolving functions of selenoproteins (containing selenium (Se) as selenocysteine) may hold the key to alleviating diseases where insults to the gastrointestinal (GI) tract are commonly seen. Using three diverse models of gut injury exemplified by dextran sodium sulfate (DSS)-induced chemical injury, GI infection by the enteropathogenic bacterium, Citrobacter rodentium, or helminth Nippostrongylus brasiliensis, the ability of the gut immune system to resolve inflammation will be examined. Studies from the last cycle demonstrated the ability of Se to effectively shunt the arachidonic acid pathway of eicosanoid metabolism from pro-inflammatory prostaglandin E2 (PGE2) towards the anti-inflammatory 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in macrophages. Such a metabolite "class switching" occurs as a result of redox changes by the way of selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-κB and peroxisome proliferator activated receptor (PPAR)-γ that impact many metabolic pathways, including the eicosanoid and L-arginine (L-Arg) pathway. As a result, selenoprotein expression was critical for polarizing pro-inflammatory M1 (Th1; classically-activated) macrophages towards an M2-like (Th2; alternatively activated) phenotype. Our studies suggest that changes in the metabolome are key to such a phenotypic switch towards reparative M2 macrophages that are endowed with anti-inflammatory and pro-resolving properties, which will be tested in three diverse models. Preliminary data suggest that selenoproteins are critical to efficiently resolve injury in all three models. Thus, our studies ar based on the overarching hypothesis that selenoprotein expression alters metabolic pathways to mitigate inflammation while promoting resolution following injury. The hypothesis will be tested using mice that lack selenoproteins in macrophages and T-cells: 1) to determine the role of selenoproteins on the pro-resolving functions of M2 macrophages following chemical injury; 2) to determine the role of selenoproteins in resolving inflammation following a Th2 mediated infection; and 3) to determine the pro-resolving functions of selenoproteins following a Th1/Th17 mediated infection. These studies will test if the pro-resolving properties of selenoproteins are dependent on the changes in the metabolome in three models of GI inflammation. The long-term goal of our studies is to understand the role of selenium in GI homeostasis is mediated through changes in the metabolism of immune cells.