Abstract
Enteropathogenic Escherichia coli (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 E2 (PGE2) toward anti-inflammatory mediators derived from PGD2, such as 15-deoxy-Δ12, 14- prostaglandin J2 (15d-PGJ2), 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 C. rodentium, 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 PGE2 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-PGJ2 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[Sec] 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.
Highlights
Gastrointestinal (GI) pathogens, such as enteropathogenic Escherichia coli (EPEC), remain a global concern [1]
We hypothesized that Se-A and Se-S mice would experience a lower bacterial burden and greater survival when compared to the Se-D mice as a result of an increased ability to mount a better immune response and increased epithelial barrier integrity
While differences were observed at days 16 and 18, most of the data were analyzed on day 11 post infection (PI), as this represented the peak of infection
Summary
Gastrointestinal (GI) pathogens, such as enteropathogenic Escherichia coli (EPEC), remain a global concern [1]. One identifying feature of these enteric infections is the formation of attaching and effacing (A/E) lesions in the colon [1, 4]. Enteric infections are characterized by inflammation of the GI tract somewhat similar to that seen in Crohn’s disease, ulcerative colitis, dysbiosis, and colon tumorigenesis [5,6,7,8,9]. The immune response that arises from its colonization of the gut mimics that of EPEC, which is associated with exacerbated inflammation as a result of the production of inflammatory cytokines such as, tumor necrosis factor (TNFα), interferon gamma (IFNγ), and interleukin (IL-6) [12]. C. rodentium is often used as a model for EPEC [1]
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