Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.

The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.

The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J 2 (15d-PGJ 2 ) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet.

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.