Cellular selenium and PGJ2 metabolism

了解微量营养素硒（Se）作为第21位氨基酸硒代半胱氨酸（Sec）并入硒蛋白的抗炎和促分解功能可能是控制炎症性肠病（IBD）患者胃肠道（GI）稳态的关键。尽管取得了进展，但对于许多IBD患者来说，完全粘膜愈合仍然是一个困难的治疗目标。对损伤的局部反应涉及第一反应者、多形核细胞（嗜中性粒细胞; PMN）和巨噬细胞，其不仅显示炎性表型，而且还通过凋亡PMN的胞浆细胞增多来帮助消退炎症，以启动涉及代谢重编程的促消退事件级联。我们已经证明了硒蛋白在有效分流巨噬细胞中花生四烯酸（ARA）代谢途径中的重要作用，通过使巨噬细胞极化向抗炎/促消退（M2）表型倾斜来实现消退。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的硒蛋白依赖性差异调节导致类花生酸类转换，导致环氧合酶（考克斯）衍生的促炎性前列腺素E2（PGE 2）减少和高PGD 2及其抗炎和促再分解的环戊烯酮前列腺素（CyPG）代谢产物，β 12-前列腺素J2和15-脱氧-β 12，14-PGJ 2，在三种胃肠道损伤模型中，包括葡聚糖硫酸钠化学损伤、啮齿类柠檬酸杆菌肠道感染和蠕虫寄生虫巴西日本圆线虫。在这些模型中，巨噬细胞硒蛋白表达是减轻炎症和增加经典活化（M1）向促消退替代活化（M2）样细胞极化的关键，所述促消退替代活化（M2）样细胞依赖于CyPG产生，表明消退。我们的研究使我们的硒蛋白，硒，高表达的硒蛋白在巨噬细胞中响应饮食硒供应。除了其在细胞周期调节中的功能外，硒在胃肠道炎症和消退中的作用还没有得到很好的理解。临床数据表明，溃疡性结肠炎患者的炎症结肠组织中的硒水平分别与健康对照组和主动缓解组相比沿着PGD 2水平降低。在令人兴奋的可行性数据的指导下，我们假设通过饮食硒和/或其他转录机制调节硒的表达，由CyPG介导，可能是增加促消退机制的关键，最终影响胃肠道损伤的粘膜愈合。我们将在缺乏SelenoW的鼠模型中测试该假设以：1）检查SelenoW在GI炎症消退中的作用; 2）检查SelenoW在炎症消退期间在巨噬细胞和PMN的相互作用中的作用;和3）检查SelenoW在炎症消退期间在代谢适应中的作用。这些研究的成功完成将提供新的信息，突出特定硒蛋白和炎症解决途径之间的相互作用，这对于增加我们对膳食硒在最佳肠道健康中的作用的理解至关重要。

Understanding the anti-inflammatory and pro-resolving functions of micronutrient selenium (Se) incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins may hold the key to controlling gastrointestinal (GI) homeostasis in patients with inflammatory bowel disease (IBD). Despite advances, complete mucosal healing remains a difficult treatment target for many patients with IBD. Localized response to injury involves first responders, polymorphonuclear cells (neutrophils; PMNs), and macrophages that not only display an inflammatory phenotype, but also aid in resolving inflammation via efferocytosis of apoptotic PMNs, to initiate a cascade of pro-resolution events involving metabolic reprogramming. We have demonstrated an essential role for selenoproteins in effectively shunting pathways of arachidonic acid (ARA) metabolism in macrophages to effect resolution by skewing macrophage polarization towards an anti-inflammatory/pro-resolutory (M2) phenotype. Selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-κB and peroxisome proliferator activated receptor (PPAR)-γ, led to eicosanoid class switching resulting in decreased cyclooxygenase (COX)-derived pro-inflammatory prostaglandin E2 (PGE2) and high PGD2 and its anti-inflammatory and pro-resolutory cyclopentenone prostaglandins (CyPGs) metabolites, ∆12-prostaglandin J2 and 15-deoxy-∆12,14-PGJ2, in three models of GI injury involving chemical injury with dextran sodium sulfate, enteric infection with bacterium Citrobacter rodentium and helminthic parasite, Nippostrongylus brasiliensis. In these models, macrophage selenoprotein expression was key to mitigating inflammation and increasing the polarization of classically activated (M1) to pro-resolving alternatively activated (M2)-like cells that was dependent on CyPG production suggesting resolution. Our studies led us to a selenoprotein, SelenoW, a highly expressed selenoprotein in macrophages in response to dietary Se supply. Apart from its function in cell cycle regulation, the role of SelenoW in GI inflammation and resolution is not well understood. Clinical data indicated that SelenoW levels in inflamed colonic tissue of ulcerative colitis patients were decreased along with PGD2 levels compared to healthy controls and those in active remission, respectively. Guided by exciting feasibility data, we hypothesize that regulation of SelenoW expression by dietary Se and/or other transcriptional mechanisms, mediated by CyPGs, may hold a key to increasing pro-resolution mechanisms to ultimately effect mucosal healing from GI injury. We will test the hypothesis in murine models lacking SelenoW to: 1) Examine the role of SelenoW in resolution of GI inflammation; 2) Examine the role of SelenoW in the interaction of macrophages and PMNs during resolution of inflammation; and 3) Examine the role of SelenoW in metabolic adaptation during resolution of inflammation. Successful completion of these studies will provide new information highlighting the interplay between specific selenoproteins and pathways of resolution of inflammation, essential to increase our understanding of the role of dietary Se in optimal gut health.