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  • Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis.

Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis.

Nature medicine (2014-03-25)
Don-Kyu Kim, Jae-Ho Jeong, Ji-Min Lee, Kwang Soo Kim, Seung-Hwan Park, Yong Deuk Kim, Minseob Koh, Minsang Shin, Yoon Seok Jung, Hyung-Seok Kim, Tae-Hoon Lee, Byung-Chul Oh, Jae Il Kim, Hwan Tae Park, Won-Il Jeong, Chul-Ho Lee, Seung Bum Park, Jung-Joon Min, Sook-In Jung, Seok-Yong Choi, Hyon E Choy, Hueng-Sik Choi
ABSTRACT

In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Iron, ≥99%, reduced, powder (fine)
Sigma-Aldrich
Carbonyl iron, ≥97% Fe basis
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Iron, powder, −325 mesh, 97%
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Iron, chips, 99.98% trace metals basis
Sigma-Aldrich
Iron, puriss. p.a., carbonyl-Iron powder, low in magnesium and manganese compounds, ≥99.5% (RT)
Sigma-Aldrich
Iron, granular, 10-40 mesh, >99.99% trace metals basis
Sigma-Aldrich
Iron, foil, thickness 0.1 mm, ≥99.9% trace metals basis
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Iron, foil, thickness 0.25 mm, ≥99.99% trace metals basis
Sigma-Aldrich
Iron, wire, diam. 1.0 mm, ≥99.9% trace metals basis
Iron, IRMM®, certified reference material, 0.5 mm wire
Iron, foil, 300x300mm, thickness 0.1mm, hard, 99.5%
Sigma-Aldrich
Iron, rod, diam. 6.3 mm, 99.98% trace metals basis
Iron, foil, 25x25mm, thickness 1.0mm, as rolled, 99.5%
Iron, foil, 100x100mm, thickness 1.0mm, as rolled, 99.99+%
Iron, foil, 25x25mm, thickness 2mm, as rolled, 99.99+%
Iron, foil, 100x100mm, thickness 0.5mm, hard, 99.5%
Iron, foil, 150x150mm, thickness 3.0mm, as rolled, 99.5%
Iron, rod, 100mm, diameter 2.0mm, as drawn, 99.95%
Iron, rod, 200mm, diameter 2.0mm, as drawn, 99.99+%
Iron, rod, 500mm, diameter 9.5mm, as drawn, soft ingot 99.8+%
Iron, foil, 10mm disks, thickness 0.01mm, 99.85%
Iron, foil, 10mm disks, thickness 0.01mm, 99.99+%
Iron, foil, 10mm disks, thickness 0.020mm, 99.85%
Iron, foil, 10mm disks, thickness 0.025mm, as rolled, 99.99+%
Iron, foil, 10mm disks, thickness 0.025mm, hard, 99.5%
Iron, foil, 10mm disks, thickness 0.038mm, hard, 99.5%
Iron, foil, 10mm disks, thickness 0.05mm, as rolled, 99.99+%
Iron, foil, 10mm disks, thickness 0.05mm, hard, 99.5%
Iron, foil, 10mm disks, thickness 0.075mm, as rolled, 99.99+%
Iron, foil, 10mm disks, thickness 0.075mm, hard, 99.5%