Cellular selenium and PGJ2 metabolism

了解微量营养素硒（Se）作为硒蛋白中的第21种氨基酸硒半胱氨酸（Sec）的抗炎和促溶解功能，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。对损伤的局部反应包括第一反应者、多形核细胞（中性粒细胞）和巨噬细胞，它们不仅表现出炎症表型，而且还通过凋亡的pmn的efferocytosis来帮助解决炎症，启动一系列涉及代谢重编程的促解决事件。我们已经证明了硒蛋白在巨噬细胞中有效地分流花生四烯酸（ARA）代谢途径中发挥重要作用，通过使巨噬细胞极化向抗炎/促溶解（M2）表型倾斜来影响溶解。硒蛋白依赖的转录因子、核因子(NF)-κ b和过氧化物酶体增殖物激活受体(PPAR)-γ的差异调节，导致类20烷类切换，导致环氧化酶（COX）衍生的促炎前列腺素E2 （PGE2）降低，PGD2及其抗炎和促分解环戊酮前列腺素（CyPGs）代谢物∆12-前列腺素J2和15-脱氧-∆12,14- pgj2升高。三种GI损伤模型包括右旋糖酐硫酸钠化学损伤、啮齿柠檬酸杆菌肠道感染和巴西尼波圆线虫肠道感染。在这些模型中，巨噬细胞硒蛋白的表达是减轻炎症和增加经典活化（M1）向促溶解替代活化（M2）样细胞的极化的关键，后者依赖于CyPG的产生，提示解决。我们的研究使我们找到了硒蛋白，硒ow，这是一种在巨噬细胞中高表达的硒蛋白，可响应膳食硒的供应。除了在细胞周期调节中的功能外，硒酸钠在胃肠道炎症和解决中的作用尚不清楚。临床数据表明，与健康对照组和积极缓解组相比，溃疡性结肠炎患者炎症结肠组织中硒酸盐水平和PGD2水平分别下降。在令人兴奋的可行性数据的指导下，我们假设膳食硒和/或其他由CyPGs介导的转录机制对硒酸盐表达的调节可能是增加促溶解机制的关键，最终影响胃肠道损伤的粘膜愈合。我们将在缺乏硒酸钠的小鼠模型中验证这一假设：1)研究硒酸钠在解决胃肠道炎症中的作用；2)研究硒酸钠在炎症消退过程中巨噬细胞与PMNs相互作用中的作用；3)研究硒ow在炎症消退过程中代谢适应中的作用。这些研究的成功完成将提供新的信息，强调特定硒蛋白与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.