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Nat Med. 2014 Apr;20(4):419-24. doi: 10.1038/nm.3483. Epub 2014 Mar 23.

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

Author information

1
1] National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. [2].
2
1] Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea. [2] Department of Molecular Medicine(BK21plus), Chonnam National University Graduate School, Gwangju, Republic of Korea. [3].
3
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
4
1] Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea. [2] Department of Molecular Medicine(BK21plus), Chonnam National University Graduate School, Gwangju, Republic of Korea.
5
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
6
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
7
Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
8
1] Department of Molecular Medicine(BK21plus), Chonnam National University Graduate School, Gwangju, Republic of Korea. [2] Department of Oral Biochemistry, Dental Science Research Institute, Chonnam National University, Gwangju, Republic of Korea.
9
Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, Republic of Korea.
10
1] School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. [2] AnyGen, Jeonnam NanoBioResearch Center, Jangseong-gun, Republic of Korea.
11
Department of Physiology, Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
12
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
13
Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
14
1] Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea. [2] Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
15
1] Department of Molecular Medicine(BK21plus), Chonnam National University Graduate School, Gwangju, Republic of Korea. [2] Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
16
1] Department of Molecular Medicine(BK21plus), Chonnam National University Graduate School, Gwangju, Republic of Korea. [2] Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, Republic of Korea.
17
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.

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.

Comment in

PMID:
24658075
DOI:
10.1038/nm.3483
[Indexed for MEDLINE]

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