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].
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].
Nat Med. 2014 Apr;20(4):419-24. doi: 10.1038/nm.3483. Epub 2014 Mar 23.
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.
针对微生物感染，防御素样肽铁调素（由 Hamp 编码）在肝细胞中的表达被诱导，以减少巨噬细胞中铁的释放。为了阐明沙门氏菌（Salmonella enterica var. Typhimurium，S. typhimurium），一种巨噬细胞内细菌，改变宿主铁代谢以维持自身生存的机制，我们研究了属于 NR3B 亚家族的核受体家族成员在小鼠肝细胞中的作用。在这里，我们报告雌激素相关受体 γ（ERRγ，由 Esrrg 编码）通过改变宿主铁稳态来调节 S. typhimurium 的巨噬细胞内增殖，并且我们证明了 ERRγ 反向激动剂具有抗菌作用。S. typhimurium 刺激白细胞介素 6 信号诱导肝 ERRγ 表达，导致铁调素诱导，最终导致小鼠低铁血症。相反，肝脏中 ERRγ mRNA 表达的缺失减弱了 S. typhimurium 介导的铁调素诱导，并使 S. typhimurium 感染引起的低铁血症正常化。ERRγ 的反向激动剂通过减少 ERRγ 介导的铁调素 mRNA 表达改善了 S. typhimurium 介导的低铁血症，并对 S. typhimurium 感染发挥了强大的抗菌作用，从而提高了宿主的存活率。总之，这些发现表明通过调节宿主铁稳态来控制多药耐药性细胞内细菌的另一种方法。
