title: 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 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.
authors.affiliation: 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].
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: 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].
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: 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.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Kwang Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Minsang
authors.initials: M
authors.lastname: Shin
authors.affiliation: 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.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.affiliation: 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.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Physiology, Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
authors.forename: Hwan Tae
authors.initials: HT
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Min
authors.affiliation: 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.
authors.forename: Sook-In
authors.initials: SI
authors.lastname: Jung
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Hyon E
authors.initials: HE
authors.lastname: Choy
authors.affiliation: 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.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism*; D064451:Hepcidins / Q000276:immunology / Q000378:metabolism*; D006706:Homeostasis; D015850:Interleukin-6 / Q000276:immunology*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*; D012480:Salmonella Infections / Q000276:immunology / Q000378:metabolism*; D012486:Salmonella typhimurium; D015398:Signal Transduction / Q000276:immunology* / Q000502:physiology; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C490916:Esrrg protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D011960:Receptors, Estrogen; D000098742:Ferroportin; D007501:Iron