AUTHOR=Nettleford Shaneice K. , Zhao Luming , Qian Fenghua , Herold Morgan , Arner Brooke , Desai Dhimant , Amin Shantu , Xiong Na , Singh Vishal , Carlson Bradley A. , Prabhu K. Sandeep 

TITLE=The Essential Role of Selenoproteins in the Resolution of Citrobacter rodentium-Induced Intestinal Inflammation

JOURNAL=Frontiers in Nutrition

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.00096

DOI=10.3389/fnut.2020.00096

ISSN=2296-861X

ABSTRACT=<p>Enteropathogenic <italic>Escherichia coli</italic> (EPEC) leads to adverse colonic inflammation associated with poor resolution of inflammation and loss of epithelial integrity. Micronutrient trace element selenium (Se) is incorporated into selenoproteins as the 21st amino acid, selenocysteine (Sec). Previous studies have shown that such an incorporation of Sec into the selenoproteome is key for the anti-inflammatory functions of Se in macrophages and other immune cells. An intriguing mechanism underlying the anti-inflammatory and pro-resolving effects of Se stems from the ability of selenoproteins to skew arachidonic acid metabolism from pro-inflammatory mediators, prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) toward anti-inflammatory mediators derived from PGD<sub>2</sub>, such as 15-deoxy-Δ<sup>12, 14</sup>- prostaglandin J<sub>2</sub> (15d-PGJ<sub>2</sub>), via eicosanoid class switching of bioactive lipids. The impact of Se and such an eicosanoid-class switching mechanism was tested in an enteric infection model of gut inflammation by <italic>C. rodentium</italic>, a murine equivalent of EPEC. C57BL/6 mice deficient in Se (Se-D) experienced higher mortality when compared to those on Se adequate (0.08 ppm Se) and Se supplemented (0.4 ppm Se) diets following infection. Decreased survival was associated with decreased group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells in colonic lamina propria of Se-D mice along with deceased expression of epithelial barrier protein Zo-1. Inhibition of metabolic inactivation of PGE<sub>2</sub> by 15-prostaglandin dehydrogenase blocked the Se-dependent increase in ILC3 and Th17 cells in addition to reducing epithelial barrier integrity, as seen by increased systemic levels of FITC-dextran following oral administration; while 15d-PGJ<sub>2</sub> administration in Se-D mice alleviated the effects by increasing ILC3 and Th17 cells. Mice lacking selenoproteins in monocyte/macrophages via the conditional deletion of the tRNA<sup>[Sec]</sup> showed increased mortality post infection. Our studies indicate a crucial role for dietary Se in the protection against inflammation following enteric infection via immune mechanisms involving epithelial barrier integrity.</p>