Cellular selenium and PGJ2 metabolism

了解微量营养素硒(Se)作为第21个氨基酸--硒半胱氨酸(Sec)--在硒蛋白中的抗炎和促分解功能，可能是控制炎症性肠病(IBD)患者胃肠(GI)内环境平衡的关键。尽管取得了进展，但对于许多IBD患者来说，完全的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、中性粒细胞(PMN)和巨噬细胞，它们不仅表现出炎症表型，而且通过吞噬凋亡的PMN来帮助化解炎症，从而启动一系列涉及代谢重编程的促分解事件。我们已经证明了硒蛋白在有效地分流巨噬细胞中花生四烯酸(ARA)代谢途径以通过将巨噬细胞极化偏向抗炎/支持(M2)表型来影响分辨率方面发挥了重要作用。在三种胃肠道损伤模型中，依赖于硒蛋白的转录因子(核因子-κB和过氧化物酶体增殖物激活受体-γ)的差异调节导致二十烷类化合物的转换，导致环氧合酶(COX)衍生的促炎前列腺素E2(PGE_2)减少和PGD_2升高，以及它的抗炎和促炎环戊酮前列腺素(CyPGs)代谢产物∆12-前列腺素J2和15-脱氧-∆12，14-PGJ2。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激活(M1)到前分解交替激活(M2)样细胞的极化的关键，这依赖于CyPG的产生提示分解。我们的研究将我们引向了一种硒蛋白，SelenoW，一种在巨噬细胞中高度表达的硒蛋白，对饮食中的硒供应做出反应。除了在细胞周期调节中的作用外，SelenoW在胃肠道炎症和消退中的作用还不是很清楚。临床资料表明，溃疡性结肠炎患者炎症结肠组织中的SelenoW水平和PGD2水平分别低于健康对照组和活动期缓解期患者。在令人兴奋的可行性数据的指导下，我们假设膳食Se和/或由CyPG介导的其他转录机制对SelenoW表达的调节可能是增加促分解机制的关键，从而最终影响胃肠道损伤的粘膜修复。我们将在缺乏SelenoW的小鼠模型中检验这一假设：1)研究SelenoW在胃肠道炎症消退中的作用；2)研究SelenoW在炎症消退过程中巨噬细胞和中性粒细胞相互作用中的作用；3)研究SelenoW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，强调特定的硒蛋白与炎症消退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.