Inflammation is a hallmark of
inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between
selenium (Se) status and IBD-induced
inflammation, our objective was to demonstrate that
selenoproteins in macrophages were essential to suppress proinflammatory mediators, in part, by the modulation of
arachidonic acid metabolism. Acute
colitis was induced using 4%
dextran sodium sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.08 ppm;
sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm;
sodium selenite) and high Se (1.0 ppm;
sodium selenite) diets. Selenocysteinyl
transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were used to examine the role of
selenoproteins in macrophages on
disease progression and severity using histopathological evaluation, expression of proinflammatory and anti-inflammatory genes, and modulation of PG metabolites in urine and plasma. Whereas Se-deficient and Se-adequate mice showed increased
colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased
colitis-associated
inflammation with an upregulation of expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of
PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of
15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of
15-PGDH, lack of
selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific
selenoproteins and upregulation of
15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving effects.
Selenoproteins in macrophages protect mice from
dextran sodium sulfate-
colitis by enhancing 15-PGDH-dependent oxidation of
PGE2 to alleviate
inflammation, suggesting a therapeutic role for Se in IBD.