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

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 macrophages1. 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.

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Figure 1: Hepatic ERRγ mediates alteration of serum iron levels following S. typhimurium infection through IL-6 signaling.
Figure 2: ERRγ induces hepcidin mRNA expression and regulates iron metabolism.
Figure 3: Inverse agonist of ERRγ, GSK5182, ameliorates S. typhimurium–mediated hypoferremia through suppression of hepcidin expression.
Figure 4: Inverse agonist of ERRγ, GSK5182, controls intracellular S. typhimurium infection.

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Acknowledgements

We would like to thank D. Moore, S. Adhya and E.-K. Jo for critical reading of the manuscript, K.A. Cho for technical assistance and M. Shong (Chungnam National University) for providing the TEL-JAK2 construct. This work was supported by a National Creative Research Initiatives Grant (20110018305) and the Future-based Technology Development Program (BIO Fields) (20100019512) through the National Research Foundation of Korea (funded by the Korean government (Ministry of Science, ICT & Future Planning)) (H.-S.C.) and by the National Research Foundation of Korea (no. 2012-0006073) (H.E.C.).

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Contributions

D.-K.K. and J.-H.J. designed and performed most of the experiments. H.-S.C. and H.E.C. supervised the project. M.K. and S.B.P. synthesized and provided GSK5182. J.I.K. synthesized and provided hepcidin peptide. C.-H.L., H.T.P., H.-S.K., T.-H.L., J.-H.J. and K.S.K., performed animal studies. Y.S.J., J.-M.L. and W.-I.J. isolated liver macrophages. J.-J.M., M.S. and S.-H.P. carried out in vivo imaging studies. B.-C.O. and Y.D.K. performed biochemical and western blot assays. D.-K.K., J.-H.J., S.-I.J., S.-Y.C., H.E.C. and H.-S.C. analyzed data and wrote the manuscript.

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Correspondence to Hyon E Choy or Hueng-Sik Choi.

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The authors declare no competing financial interests.

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Kim, DK., Jeong, JH., Lee, JM. et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med 20, 419–424 (2014). https://doi.org/10.1038/nm.3483

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