Cellular Selenium Status and PGJ2 Metabolism

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 DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that underlie the pro-resolving functions of selenoproteins (containing selenium (Se) as selenocysteine) may hold the key to alleviating diseases where insults to the gastrointestinal (GI) tract are commonly seen. Using three diverse models of gut injury exemplified by dextran sodium sulfate (DSS)-induced chemical injury, GI infection by the enteropathogenic bacterium, Citrobacter rodentium, or helminth Nippostrongylus brasiliensis, the ability of the gut immune system to resolve inflammation will be examined. Studies from the last cycle demonstrated the ability of Se to effectively shunt the arachidonic acid pathway of eicosanoid metabolism from pro-inflammatory prostaglandin E2 (PGE2) towards the anti-inflammatory 15-deoxy-12,14-PGJ2 (15d-PGJ2) in macrophages. Such a metabolite "class switching" occurs as a result of redox changes by the way of selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-B and peroxisome proliferator activated receptor (PPAR)-that impact many metabolic pathways, including the eicosanoid and L-arginine (L-Arg) pathway. As a result, selenoprotein expression was critical for polarizing pro-inflammatory M1 (Th1; classically-activated) macrophages towards an M2-like (Th2; alternatively activated) phenotype. Our studies suggest that changes in the metabolome are key to such a phenotypic switch towards reparative M2 macrophages that are endowed with anti-inflammatory and pro-resolving properties, which will be tested in three diverse models. Preliminary data suggest that selenoproteins are critical to efficiently resolve injury in all three models. Thus, our studies ar based on the overarching hypothesis that selenoprotein expression alters metabolic pathways to mitigate inflammation while promoting resolution following injury. The hypothesis will be tested using mice that lack selenoproteins in macrophages and T-cells: 1) to determine the role of selenoproteins on the pro-resolving functions of M2 macrophages following chemical injury; 2) to determine the role of selenoproteins in resolving inflammation following a Th2 mediated infection; and 3) to determine the pro-resolving functions of selenoproteins following a Th1/Th17 mediated infection. These studies will test if the pro-resolving properties of selenoproteins are dependent on the changes in the metabolome in three models of GI inflammation. The long-term goal of our studies is to understand the role of selenium in GI homeostasis is mediated through changes in the metabolism of immune cells.